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Entry
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- *130130 - ELASTASE, NEUTROPHIL-EXPRESSED; ELANE
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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">*130130</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="#geneFunction">Gene Function</a>
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#history">History</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/130130">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div 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=ENSG00000197561;t=ENST00000263621" 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=1991" 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=130130" 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 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=ENSG00000197561;t=ENST00000263621" 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_001972" 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_001972" 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=130130" 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=00554&isoform_id=00554_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/ELANE" 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/34533,119292,182051,182056,219923,296665,307123,386981,1335212,4503549,46361516,50959888,50960680,119589995,186461558,2462491724,2462491726,2462563633,2462563635" 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/P08246" 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=1991" 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=ENSG00000197561;t=ENST00000263621" 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=ELANE" 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=ELANE" 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+1991" 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/ELANE" 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:1991" 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/1991" 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=chr19&hgg_gene=ENST00000263621.2&hgg_start=852303&hgg_end=856243&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:3309" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:3309" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/elane" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=130130[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=130130[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/ENSG00000197561" 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=ELANE" 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=ELANE" 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=ELANE" 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="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://structure.bmc.lu.se/idbase/ELA2base/" title="ELA2base: Mutation registry for Cyclic and congenital neutropenia" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">ELA2base: Mutation registr…</a></div><div style="margin-left: 0.5em;"><a href="https://research.cchmc.org/LOVD2/home.php?select_db=ELANE" title="CCHMC - Human Genetics Mutation Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">CCHMC - Human Genetics Mut…</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=ELANE&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/PA27735" 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:3309" 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:2679229" 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/ELANE#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:2679229" 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/1991/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=1991" 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>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:1991" 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=ELANE&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 191347008<br />
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<strong>ICD10CM:</strong> D70.4<br />
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<strong>ICD9CM:</strong> 288.02<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
|
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130130
|
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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ELASTASE, NEUTROPHIL-EXPRESSED; ELANE
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
ELASTASE 2; ELA2<br />
|
|
ELASTASE, NEUTROPHIL; NE<br />
|
|
HNE<br />
|
|
ELASTASE, LEUKOCYTE<br />
|
|
HLE<br />
|
|
MEDULLASIN<br />
|
|
PROTEASE, SERINE, BONE MARROW
|
|
</span>
|
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</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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<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=ELANE" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ELANE</a></em></strong>
|
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</span>
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/19/32?start=-3&limit=10&highlight=32">19p13.3</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr19:852303-856243&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'})">19:852,303-856,243</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<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
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=162800,202700" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/19/32?start=-3&limit=10&highlight=32">
|
|
19p13.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Neutropenia, cyclic
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/162800"> 162800 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
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|
|
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|
|
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</tr>
|
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|
|
|
|
|
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|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Neutropenia, severe congenital 1, autosomal dominant
|
|
|
|
</span>
|
|
</td>
|
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<td>
|
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<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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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>Neutrophil elastase (<a href="https://enzyme.expasy.org/EC/3.4.21.37" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 3.4.21.37</a>) is a serine protease of neutrophil and monocyte granules (<a href="#20" class="mim-tip-reference" title="Horwitz, M., Benson, K. F., Person, R. E., Aprikyan, A. G., Dale, D. C. <strong>Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis.</strong> Nature Genet. 23: 433-436, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10581030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10581030</a>] [<a href="https://doi.org/10.1038/70544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10581030">Horwitz et al., 1999</a>). Its key physiologic role is in innate host defense, but it can also participate in tissue remodeling and possesses secretagogue actions important to local inflammatory responses (<a href="#14" class="mim-tip-reference" title="Chua, F., Laurent, G. J. <strong>Neutrophil elastase: mediator of extracellular matrix destruction and accumulation.</strong> Proc. Am. Thorac. Soc. 3: 424-427, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16799086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16799086</a>] [<a href="https://doi.org/10.1513/pats.200603-078AW" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16799086">Chua and Laurent, 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16799086+10581030" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#3" class="mim-tip-reference" title="Aoki, Y. <strong>Crystallization and characterization of a new protease in mitochondria of bone marrow cells.</strong> J. Biol. Chem. 253: 2026-2032, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/632253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">632253</a>]" pmid="632253">Aoki (1978)</a> purified a 31-kD serine protease from human bone marrow cell mitochondria. Both granulocytes and erythroblasts were found to contain the protease medullasin, but it was not detected in lymphocytes or thrombocytes. It was shown to be located on the inner membrane of mitochondria. <a href="#28" class="mim-tip-reference" title="Nakamura, H., Okano, K., Aoki, Y., Shimizu, H., Naruto, M. <strong>Nucleotide sequence of human bone marrow serine protease (medullasin) gene.</strong> Nucleic Acids Res. 15: 9601-9602, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3479752/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3479752</a>] [<a href="https://doi.org/10.1093/nar/15.22.9601" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3479752">Nakamura et al. (1987)</a> reported the complete genomic sequence and deduced the amino acid sequence of the medullasin precursor. It contains 267 amino acids, including a possible leader sequence of 29 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3479752+632253" 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="#17" class="mim-tip-reference" title="Fletcher, T. S., Shen, W.-F., Largman, C. <strong>Primary structure of human pancreatic elastase 2 determined by sequence analysis of the cloned mRNA.</strong> Biochemistry 26: 7256-7261, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3427074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3427074</a>] [<a href="https://doi.org/10.1021/bi00397a010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3427074">Fletcher et al. (1987)</a> cloned a cDNA encoding elastase-2 from a human pancreatic cDNA library. Similarities to and differences from elastase-1 (<a href="/entry/130120">130120</a>) and the chymotrypsins (e.g., <a href="/entry/118890">118890</a>) were described. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3427074" 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="Kawashima, I., Tani, T., Shimoda, K., Takiguchi, Y. <strong>Characterization of pancreatic elastase II cDNAs: two elastase II mRNAs are expressed in human pancreas.</strong> DNA 6: 163-172, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3646943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3646943</a>] [<a href="https://doi.org/10.1089/dna.1987.6.163" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3646943">Kawashima et al. (1987)</a> isolated cDNAs from a human pancreatic cDNA library, which indicated that at least 2 elastase II messages are expressed in pancreas. The 2 human elastases II have been designated IIA and IIB. There is 90% overall homology between the amino acid sequences of these 2 classes of elastase II, which is synthesized as a preproenzyme of 269 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3646943" 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="#36" class="mim-tip-reference" title="Sinha, S., Watorek, W., Karr, S., Giles, J., Bode, W., Travis, J. <strong>Primary structure of human neutrophil elastase.</strong> Proc. Nat. Acad. Sci. 84: 2228-2232, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3550808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3550808</a>] [<a href="https://doi.org/10.1073/pnas.84.8.2228" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3550808">Sinha et al. (1987)</a> determined the complete amino acid sequence of human neutrophil elastase. The protein consists of 218 amino acid residues, contains 2 asparagine-linked carbohydrate side chains, and is joined together by 2 disulfide bonds. There is only moderate homology with porcine pancreatic elastase (43%). <a href="#29" class="mim-tip-reference" title="Okano, K., Aoki, Y., Sakurai, T., Kajitani, M., Kanai, S., Shimazu, T., Shimizu, H., Naruto, M. <strong>Molecular cloning of complementary DNA for human medullasin: an inflammatory serine protease in bone marrow cells.</strong> J. Biochem. 102: 13-16, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2822677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2822677</a>] [<a href="https://doi.org/10.1093/oxfordjournals.jbchem.a122024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2822677">Okano et al. (1987)</a> showed that the 218-amino acid sequence of human neutrophil elastase is identical to that of medullasin. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2822677+3550808" 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="#5" class="mim-tip-reference" title="Belaaouaj, A., Kim, K. S., Shapiro, S. D. <strong>Degradation of outer membrane protein A in Escherichia coli killing by neutrophil elastase.</strong> Science 289: 1185-1187, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10947984/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10947984</a>] [<a href="https://doi.org/10.1126/science.289.5482.1185" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10947984">Belaaouaj et al. (2000)</a> determined the mechanism of neutrophil elastase-mediated killing of E. coli. They found that neutrophil elastase degraded outer membrane protein A (OmpA), localized on the surface of gram-negative bacteria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10947984" 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="Weinrauch, Y., Drujan, D., Shapiro, S. D., Weiss, J., Zychlinsky, Z. <strong>Neutrophil elastase targets virulence factors of enterobacteria.</strong> Nature 417: 91-94, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12018205/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12018205</a>] [<a href="https://doi.org/10.1038/417091a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12018205">Weinrauch et al. (2002)</a> identified human neutrophil elastase as a key host defense protein in preventing the escape of Shigella from phagocytic vacuoles in neutrophils. Neutrophil elastase degrades Shigella virulence factors at a 1,000-fold lower concentration than that needed to degrade other bacterial proteins. In neutrophils in which neutrophil elastase is inactivated pharmacologically or genetically, Shigella escapes from phagosomes, increasing bacterial survival. Neutrophil elastase also preferentially cleaves virulence factors of Salmonella and Yersinia. <a href="#39" class="mim-tip-reference" title="Weinrauch, Y., Drujan, D., Shapiro, S. D., Weiss, J., Zychlinsky, Z. <strong>Neutrophil elastase targets virulence factors of enterobacteria.</strong> Nature 417: 91-94, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12018205/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12018205</a>] [<a href="https://doi.org/10.1038/417091a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12018205">Weinrauch et al. (2002)</a> concluded that their findings established neutrophil elastase as the first neutrophil factor that targets bacterial virulence proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12018205" 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>Increased leukocyte elastase activity in mice lacking secretory leukocyte protease inhibitor (SLPI; <a href="/entry/107285">107285</a>) leads to impaired wound healing due to enhanced activity of transforming growth factor-beta (<a href="/entry/190180">190180</a>) and perhaps additional mechanisms (<a href="#4" class="mim-tip-reference" title="Ashcroft, G. S., Lei, K., Jin, W., Longenecker, G., Kulkarni, A. B., Greenwell-Wild, T., Hale-Donze, H., McGrady, G., Song, X.-Y., Wahl, S. M. <strong>Secretory leukocyte protease inhibitor mediates non-redundant functions necessary for normal wound healing.</strong> Nature Med. 6: 1147-1153, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11017147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11017147</a>] [<a href="https://doi.org/10.1038/80489" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11017147">Ashcroft et al., 2000</a>). Proepithelin (PEPI; <a href="/entry/138945">138945</a>), also known as progranulin, an epithelial growth factor, can be converted to epithelins (EPIs) in vivo. <a href="#40" class="mim-tip-reference" title="Zhu, J., Nathan, C., Jin, W., Sim, D., Ashcroft, G. S., Wahl, S. M., Lacomis, L., Erdjument-Bromage, H., Tempst, P., Wright, C. D., Ding, A. <strong>Conversion of proepithelin to epithelins: roles of SLPI and elastase in host defense and wound repair.</strong> Cell 111: 867-878, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12526812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12526812</a>] [<a href="https://doi.org/10.1016/s0092-8674(02)01141-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12526812">Zhu et al. (2002)</a> found that PEPI and EPIs exert opposing activities. EPIs inhibited the growth of epithelial cells but induced them to secrete the neutrophil attractant interleukin-8 (IL8; <a href="/entry/146930">146930</a>), while PEPI blocked neutrophil activation by tumor necrosis factor (TNF; <a href="/entry/191160">191160</a>), preventing release of oxidants and proteases. SLPI and PEPI formed complexes, preventing elastase from converting PEPI to EPIs. Supplying PEPI corrected the wound-healing defect in Slpi null mice. The authors concluded that SLPI/elastase act via PEPI/EPIs to operate a switch at the interface between innate immunity and wound healing. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12526812+11017147" 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 fusion protein PML (<a href="/entry/102578">102578</a>)-RARA (<a href="/entry/180240">180240</a>), which is generated by the t(15;17)(q22;q11.2) translocation associated with acute promyelocytic leukemia (APL; <a href="/entry/612376">612376</a>), initiates APL when expressed in the early myeloid compartment of transgenic mice. <a href="#24" class="mim-tip-reference" title="Lane, A. A., Ley, T. J. <strong>Neutrophil elastase cleaves PML-RAR-alpha and is important for the development of acute promyelocytic leukemia in mice.</strong> Cell 115: 305-318, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14636558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14636558</a>] [<a href="https://doi.org/10.1016/s0092-8674(03)00852-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14636558">Lane and Ley (2003)</a> found that PML-RARA was cleaved in several positions by a neutral serine protease in a human myeloid cell line; purification revealed that the protease was ELA2. Immunofluorescence localization studies suggested that cleavage of PML-RARA must have occurred within the cell, perhaps within the nucleus. The functional importance of ELA2 for APL development was assessed in Ela2-deficient mice. More than 90% of bone marrow PML-RARA-cleaving activity was lost in the absence of Ela2, and Ela2-deficient animals, but not cathepsin G (CTSG; <a href="/entry/116830">116830</a>)-deficient animals, were protected from APL development. The authors determined that primary mouse and human APL cells also contained ELA2-dependent PML-RARA-cleaving activity. <a href="#24" class="mim-tip-reference" title="Lane, A. A., Ley, T. J. <strong>Neutrophil elastase cleaves PML-RAR-alpha and is important for the development of acute promyelocytic leukemia in mice.</strong> Cell 115: 305-318, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14636558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14636558</a>] [<a href="https://doi.org/10.1016/s0092-8674(03)00852-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14636558">Lane and Ley (2003)</a> concluded that, since ELA2 is maximally produced in promyelocytes, it may play a role in APL pathogenesis by facilitating the leukemogenic potential of PML-RARA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14636558" 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 reporter gene assays in transfected NIH3T3 mouse fibroblasts, <a href="#35" class="mim-tip-reference" title="Salipante, S. J., Rojas, M. E. B., Korkmaz, B., Duan, Z., Wechsler, J., Benson, K. F., Person, R. E., Grimes, H. L., Horwitz, M. S. <strong>Contributions to neutropenia from PFAAP5 (N4BP2L2), a novel protein mediating transcriptional repressor cooperation between Gfi1 and neutrophil elastase.</strong> Molec. Cell. Biol. 29: 4394-4405, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19506020/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19506020</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19506020[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.00596-09" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19506020">Salipante et al. (2009)</a> found that nuclear ELA2 potentiated transcriptional repression by GFI1 (<a href="/entry/600871">600871</a>). ELA2 did not function independently as a transcriptional repressor, and corepression with GFI1 did not require proteolytically active ELA2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19506020" 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 the LSL-Kras-G12D (<a href="/entry/191170#0005">191170.0005</a>) model of mouse lung adenocarcinoma (<a href="/entry/211980">211980</a>), <a href="#21" class="mim-tip-reference" title="Houghton, A. M., Rzymkiewicz, D. M., Ji, H., Gregory, A. D., Egea, E. E., Metz, H. E., Stolz, D. B., Land, S. R., Marconcini, L. A., Kliment, C. R., Jenkins, K. M., Beaulieu, K. A., Mouded, M., Frank, S. J., Wong, K. K., Shapiro, S. D. <strong>Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth.</strong> Nature Med. 16: 219-223, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20081861/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20081861</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20081861[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm.2084" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20081861">Houghton et al. (2010)</a> found that mutant mice who were also Elane -/- had markedly decreased tumor burden compared to Elane +/+ mice. All LSL-Kras/Elane +/+ mice died, whereas none of the Elane -/- mice died in the study period. In vitro studies in human and mouse adenocarcinoma cells showed that neutrophil elastase directly induced tumor cell proliferation at physiologic levels by gaining access to an endosomal compartment within tumor cells, where it degraded insulin receptor substrate-1 (IRS1; <a href="/entry/147545">147545</a>). Degradation of IRS1 was associated with increased interaction between PI3K (see <a href="/entry/171834">171834</a>) and the potent mitogen PDGFR (<a href="/entry/173410">173410</a>), skewing the PI3K axis toward tumor cell proliferation. The findings identified IRS1 as a key regulator of PI3K within malignant cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20081861" 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 yeast 2-hybrid analysis, in vitro pull-down assays, and in vivo immunoprecipitation experiments, <a href="#16" class="mim-tip-reference" title="Duan, Z., Li, F.-Q., Wechsler, J., Meade-White, K., Williams, K., Benson, K. F., Horwitz, M. <strong>A novel Notch protein, N2N, targeted by neutrophil elastase and implicated in hereditary neutropenia.</strong> Molec. Cell. Biol. 24: 58-70, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14673143/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14673143</a>] [<a href="https://doi.org/10.1128/MCB.24.1.58-70.2004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14673143">Duan et al. (2004)</a> demonstrated that human NOTCH2NLA (<a href="/entry/618023">618023</a>) interacted with NE containing a processed N terminus and an intact C terminus. The interaction was mediated by the C terminus of NE and the C-terminal 24-amino acid (C24) domain of NOTCH2NLA. NE proteolytically cleaved NOTCH2NLA within its EGF repeats in vitro and in vivo, and the C24 domain of NOTCH2NLA appeared to provide resistance to NE protease activity. In vitro analyses showed that NOTCH2NLA repressed the transcriptional activities of Notch proteins. Disease-causing NE mutants disrupted interaction of NE with NOTCH2NLA, impaired proteolysis of NOTCH2NLA and NOTCH2 (<a href="/entry/600275">600275</a>), and interfered with NOTCH2 signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14673143" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Role in Human Immunodeficiency Virus-1 Infection</em></strong></p><p>
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<a href="#10" class="mim-tip-reference" title="Bristow, C. L., Fiscus, S. A., Flood, P. M., Arnold, R. R. <strong>Inhibition of HIV-1 by modification of a host membrane protease.</strong> Int. Immun. 7: 239-249, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7734419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7734419</a>] [<a href="https://doi.org/10.1093/intimm/7.2.239" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7734419">Bristow et al. (1995)</a> found that human, but not murine, epithelial and leukocyte elastase bound the fusion domain of human immunodeficiency virus (HIV)-1 gp160 and interacted with a pentapeptide representative of the HIV-1 fusion domain. HIV-1 infectivity was blocked during, but not after, the initial contact between virus and cells. <a href="#10" class="mim-tip-reference" title="Bristow, C. L., Fiscus, S. A., Flood, P. M., Arnold, R. R. <strong>Inhibition of HIV-1 by modification of a host membrane protease.</strong> Int. Immun. 7: 239-249, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7734419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7734419</a>] [<a href="https://doi.org/10.1093/intimm/7.2.239" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7734419">Bristow et al. (1995)</a> suggested that the elastase present on T-cell membranes participates in permissiveness of host cells to infection. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7734419" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Bristow, C. L. <strong>Slow human immunodeficiency virus (HIV) infectivity correlated with low HIV coreceptor levels.</strong> Clin. Diagn. Lab. Immun. 8: 932-936, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11527806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11527806</a>] [<a href="https://doi.org/10.1128/CDLI.8.5.932-936.2001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11527806">Bristow (2001)</a> found that decreased HIV infectivity correlated significantly with decreased cell surface expression of HLE on monocytes but not lymphocytes. Decreased levels of alpha-1-antitrypsin (AAT; <a href="/entry/107400">107400</a>), also known as protease inhibitor (PI), correlated with increased cell surface HLE expression and increased HIV infectivity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11527806" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Bristow, C. L., Patel, H., Arnold, R. R. <strong>Self antigen prognostic for human immunodeficiency virus disease progression.</strong> Clin. Diagn. Lab. Immun. 8: 937-942, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11527807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11527807</a>] [<a href="https://doi.org/10.1128/CDLI.8.5.937-942.2001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11527807">Bristow et al. (2001)</a> showed that decreased HIV viral load correlated with decreased circulating PI. Furthermore, asymptomatic patients manifested deficient levels of active PI. <a href="#12" class="mim-tip-reference" title="Bristow, C. L., Patel, H., Arnold, R. R. <strong>Self antigen prognostic for human immunodeficiency virus disease progression.</strong> Clin. Diagn. Lab. Immun. 8: 937-942, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11527807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11527807</a>] [<a href="https://doi.org/10.1128/CDLI.8.5.937-942.2001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11527807">Bristow et al. (2001)</a> noted that deficient levels of PI lead to degenerative lung diseases and suggested that preventing PI deficiency may prevent HIV-associated pathophysiology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11527807" 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 subclones of monocytic cell lines, <a href="#11" class="mim-tip-reference" title="Bristow, C. L., Mercatante, D. R., Kole, R. <strong>HIV-1 preferentially binds receptors copatched with cell-surface elastase.</strong> Blood 102: 4479-4486, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12933574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12933574</a>] [<a href="https://doi.org/10.1182/blood-2003-05-1635" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12933574">Bristow et al. (2003)</a> showed that HLE localized to the cell surface, but not granules, of HIV-1-permissive clones, and to the granules, but not the cell surface, of HIV-1-nonpermissive clones. Stimulation of nonpermissive clones with lipopolysaccharide and LBP (<a href="/entry/151990">151990</a>), followed by exogenous PI, induced cell surface HLE expression, resulting in susceptibility to HIV infection. PI appeared to promote HIV coreceptor colocalization with surface HLE, thus permitting HIV infectivity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12933574" 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="#41" class="mim-tip-reference" title="Zimmer, M., Medcalf, R. L., Fink, T. M., Mattmann, C., Lichter, P., Jenne, D. E. <strong>Three human elastase-like genes coordinately expressed in the myelomonocyte lineage are organized as a single genetic locus on 19pter.</strong> Proc. Nat. Acad. Sci. 89: 8215-8219, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1518849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1518849</a>] [<a href="https://doi.org/10.1073/pnas.89.17.8215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1518849">Zimmer et al. (1992)</a> demonstrated that the genes encoding azurocidin (NAZC; <a href="/entry/162815">162815</a>), proteinase-3 (PRTN3; <a href="/entry/177020">177020</a>), and neutrophil elastase each have 5 exons. All 3 genes are expressed coordinately and their protein products are packaged together at high levels into azurophil granules during neutrophil differentiation. <a href="#7" class="mim-tip-reference" title="Belaaouaj, A., Walsh, B. C., Jenkins, N. A., Copeland, N. G., Shapiro, S. D. <strong>Characterization of the mouse neutrophil elastase gene and localization to chromosome 10.</strong> Mammalian Genome 8: 5-8, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9021140/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9021140</a>] [<a href="https://doi.org/10.1007/s003359900337" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9021140">Belaaouaj et al. (1997)</a> demonstrated that the murine homolog of human ELA2 also contains 5 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1518849+9021140" 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="#41" class="mim-tip-reference" title="Zimmer, M., Medcalf, R. L., Fink, T. M., Mattmann, C., Lichter, P., Jenne, D. E. <strong>Three human elastase-like genes coordinately expressed in the myelomonocyte lineage are organized as a single genetic locus on 19pter.</strong> Proc. Nat. Acad. Sci. 89: 8215-8219, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1518849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1518849</a>] [<a href="https://doi.org/10.1073/pnas.89.17.8215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1518849">Zimmer et al. (1992)</a> showed that the NAZC, PRTN3, and ELA2 genes are within an approximately 50-kb cluster on chromosome 19pter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1518849" 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 interphase studies with differentially labeled probes for fluorescence in situ hybridization, <a href="#30" class="mim-tip-reference" title="Pilat, D., Fink, T., Obermaier-Skrobanek, B., Zimmer, M., Wekerle, H., Lichter, P., Jenne, D. E. <strong>The human Met-ase gene (GZMM): structure, sequence, and close physical linkage to the serine protease gene cluster on 19p13.3.</strong> Genomics 24: 445-450, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7713495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7713495</a>] [<a href="https://doi.org/10.1006/geno.1994.1651" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7713495">Pilat et al. (1994)</a> demonstrated that ELA2 is in a gene cluster on 19p13.3 with azurocidin, proteinase-3, and granzyme M (<a href="/entry/600311">600311</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7713495" 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 interspecific backcross analysis, <a href="#7" class="mim-tip-reference" title="Belaaouaj, A., Walsh, B. C., Jenkins, N. A., Copeland, N. G., Shapiro, S. D. <strong>Characterization of the mouse neutrophil elastase gene and localization to chromosome 10.</strong> Mammalian Genome 8: 5-8, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9021140/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9021140</a>] [<a href="https://doi.org/10.1007/s003359900337" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9021140">Belaaouaj et al. (1997)</a> mapped the mouse Ela2 gene to chromosome 10. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9021140" 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>Cyclic neutropenia (<a href="/entry/162800">162800</a>), also known as cyclic hematopoiesis, is an autosomal dominant disorder in which blood-cell production from the bone marrow oscillates with 21-day periodicity. Circulating neutrophils vary between almost normal numbers and zero. During intervals of neutropenia, affected individuals are at risk for opportunistic infection. Monocytes, platelets, lymphocytes, and reticulocytes also cycle with the same frequency. <a href="#20" class="mim-tip-reference" title="Horwitz, M., Benson, K. F., Person, R. E., Aprikyan, A. G., Dale, D. C. <strong>Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis.</strong> Nature Genet. 23: 433-436, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10581030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10581030</a>] [<a href="https://doi.org/10.1038/70544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10581030">Horwitz et al. (1999)</a> used a genomewide screen and positional cloning to map the locus to 19p13.3. They identified 7 different single-basepair substitutions in the ELA2 gene, each on a unique haplotype, in 13 of 13 families, as well as a new mutation in a sporadic case (e.g., <a href="#0001">130130.0001</a>-<a href="#0005">130130.0005</a>). Neutrophil elastase is a target for protease inhibition by alpha-1-antitrypsin (AAT; <a href="/entry/107400">107400</a>), and its unopposed release destroys tissue at sites of inflammation. <a href="#20" class="mim-tip-reference" title="Horwitz, M., Benson, K. F., Person, R. E., Aprikyan, A. G., Dale, D. C. <strong>Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis.</strong> Nature Genet. 23: 433-436, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10581030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10581030</a>] [<a href="https://doi.org/10.1038/70544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10581030">Horwitz et al. (1999)</a> hypothesized that a perturbed interaction between neutrophil elastase and serpins or other substrates may regulate mechanisms governing the clock-like timing of hematopoiesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10581030" 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>After mutations in the ELA2 gene were identified as the basis of autosomal dominant cyclic neutropenia, <a href="#15" class="mim-tip-reference" title="Dale, D. C., Person, R. E., Bolyard, A. A., Aprikyan, A. G., Bos, C., Bonilla, M. A., Boxer, L. A., Kannourakis, G., Zeidler, C., Welte, K., Benson, K. F., Horwitz, M. <strong>Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia.</strong> Blood 96: 2317-2322, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11001877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11001877</a>]" pmid="11001877">Dale et al. (2000)</a> hypothesized that congenital neutropenia (<a href="/entry/202700">202700</a>) is also due to mutation in this gene. In cyclic neutropenia, the mutations appeared to cluster near the active site of the molecule, whereas the opposite face was predominantly affected by the mutations found in congenital neutropenia. Their studies revealed that 22 of 25 patients with congenital neutropenia had 18 different heterozygous mutations. All 4 patients with cyclic neutropenia and none of 3 patients with Shwachman-Diamond syndrome (<a href="/entry/260400">260400</a>) had mutations of the ELA2 gene. In the congenital neutropenia patients, 5 different mutations were found in families with 2 or more affected members. Three instances of father-daughter pairs, 1 mother-son pair, and 1 mother with 2 affected sons by different fathers suggested autosomal dominant inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11001877" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Because all of the mutations in the ELA2 gene associated with severe congenital neutropenia had been heterozygous, <a href="#1" class="mim-tip-reference" title="Ancliff, P. J., Gale, R. E., Liesner, R., Hann, I. M., Linch, D. C. <strong>Mutations in the ELA2 gene encoding neutrophil elastase are present in most patients with sporadic severe congenital neutropenia but only in some patients with the familial form of the disease.</strong> Blood 98: 2645-2650, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11675333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11675333</a>] [<a href="https://doi.org/10.1182/blood.v98.9.2645" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11675333">Ancliff et al. (2001)</a> conducted a study to determine whether mutations in ELA2 could account for the disease phenotype in classic autosomal recessive severe congenital neutropenia (Kostmann disease; <a href="/entry/610738">610738</a>), as well as in the sporadic and autosomal dominant types. They used direct automated sequencing to study all 5 exons of ELA2 and their flanking introns in 18 patients (3 autosomal recessive, 5 autosomal dominant from 3 kindreds, and 10 sporadic). No mutations were found in the autosomal recessive families. A point mutation was identified in 1 of 3 autosomal dominant families, and a base substitution was identified in 8 of 10 patients with the sporadic form, although 1 of the 8 was shown to have a low frequency polymorphism. These results suggested that mutations in ELA2 are not responsible for classic autosomal recessive Kostmann disease, but provided further evidence for the role of ELA2 in the autosomal dominant form of severe congenital neutropenia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11675333" 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="#2" class="mim-tip-reference" title="Ancliff, P. J., Gale, R. E., Watts, M. J., Liesner, R., Hann, I. M., Strobel, S., Linch, D. C. <strong>Paternal mosaicism proves the pathogenic nature of mutations in neutrophil elastase in severe congenital neutropenia.</strong> Blood 100: 707-709, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12091371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12091371</a>] [<a href="https://doi.org/10.1182/blood-2002-01-0060" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12091371">Ancliff et al. (2002)</a> described the case of a healthy father of a patient who was demonstrated to be mosaic for his daughter's cys42-to-arg ELA2 mutation (<a href="#0009">130130.0009</a>). Semiquantitative PCR showed that approximately half of his T cells carried the mutation, in contrast to less than 10% of neutrophils. Individual hematopoietic colonies grown from peripheral blood were heterozygous for the mutation or were homozygous wildtype. The results demonstrated that precursors containing the mutation are selectively lost during myelopoiesis or fail to develop into neutrophils. <a href="#2" class="mim-tip-reference" title="Ancliff, P. J., Gale, R. E., Watts, M. J., Liesner, R., Hann, I. M., Strobel, S., Linch, D. C. <strong>Paternal mosaicism proves the pathogenic nature of mutations in neutrophil elastase in severe congenital neutropenia.</strong> Blood 100: 707-709, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12091371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12091371</a>] [<a href="https://doi.org/10.1182/blood-2002-01-0060" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12091371">Ancliff et al. (2002)</a> stated that this was the first in vivo confirmation of the pathogenic nature of elastase mutations in humans. The normal neutrophil count in the father suggested that the mutant elastase does not have paracrine effects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12091371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="Thusberg, J., Vihinen, M. <strong>Bioinformatic analysis of protein structure-function relationships: case study of leukocyte elastase (ELA2) missense mutations.</strong> Hum. Mutat. 27: 1230-1243, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16986121/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16986121</a>] [<a href="https://doi.org/10.1002/humu.20407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16986121">Thusberg and Vihinen (2006)</a> reported detailed bioinformatic analyses of 32 different pathogenic missense mutations in the ELA2 gene. Using 31 different analytic methods, the authors found that different mutations resulted in diverse deleterious effects on protein structure and function, including changes in electrostatic surface potential, contacts and stability, and aggregation, among other changes. There were no obvious genotype/phenotype correlations to explain the phenotypic expression of cyclic versus congenital neutropenia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16986121" 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="#34" class="mim-tip-reference" title="Salipante, S. J., Benson, K. F., Luty, J., Hadavi, V., Kariminejad, R., Kariminejad, M. H., Rezaei, N., Horwitz, M. S. <strong>Double de novo mutations of ELA2 in cyclic and severe congenital neutropenia.</strong> Hum. Mutat. 28: 874-881, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436313</a>] [<a href="https://doi.org/10.1002/humu.20529" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17436313">Salipante et al. (2007)</a> reported 2 unrelated patients with cyclic neutropenia and severe congenital neutropenia, respectively, who each had 2 de novo mutations in cis in the ELA2 gene (see, e.g., <a href="#0010">130130.0010</a>). In both patients, the 2 mutations were paternally derived and likely arose during spermatogenesis. Functional expression studies showed reduced proteolytic activity, evidence for induction of the unfolded protein response, and disturbed subcellular localization consistent with protein mistrafficking. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17436313" 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="#22" class="mim-tip-reference" title="Ishikawa, N., Okada, S., Miki, M., Shirao, K., Kihara, H., Tsumura, M., Nakamura, K., Kawaguchi, H., Ohtsubo, M., Yasunaga, S., Matsubara, K., Sako, M., Hara, J., Shiohara, M., Kojima, S., Sato, T., Takihara, Y., Kobayashi, M. <strong>Neurodevelopmental abnormalities associated with severe congenital neutropenia due to the R86X mutation in the HAX1 gene.</strong> J. Med. Genet. 45: 802-807, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18611981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18611981</a>] [<a href="https://doi.org/10.1136/jmg.2008.058297" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18611981">Ishikawa et al. (2008)</a> identified heterozygous mutations in the ELA2 gene in 11 (61%) of 18 Japanese patients with severe congenital neutropenia. Five (28%) patients had SCN3 (<a href="/entry/610738">610738</a>) due to mutation in the HAX1 gene (<a href="/entry/605998">605998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18611981" 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="#19" class="mim-tip-reference" title="Grenda, D. S., Murakami, M., Ghatak, J., Xia, J., Boxer, L. A., Dale, D., Dinauer, M. C., Link, D. C. <strong>Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis.</strong> Blood 110: 4179-4187, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17761833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17761833</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17761833[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/10.1182/blood-2006-11-057299" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17761833">Grenda et al. (2007)</a> demonstrated significant activation of the unfolded protein response (UPR) and cellular apoptosis in cells derived from patients with SCN1 and in human granulocyte precursors specifically transfected with SCN1-associated ELA2 mutations, including V72M (<a href="#0007">130130.0007</a>), P110L (<a href="#0006">130130.0006</a>), and G185R (<a href="#0011">130130.0011</a>). The UPR response was assessed by increased expression of XBP1 (<a href="/entry/194355">194355</a>) and HSPA5 (<a href="/entry/138120">138120</a>). Milder effects were observed with the cyclic neutropenia-associated R191Q (<a href="#0001">130130.0001</a>) mutation. There was no evidence for protein mistrafficking within the cell. The findings indicated that the magnitude of UPR activation and apoptosis induced by ELA2 mutations correlated with the phenotypic severity. <a href="#19" class="mim-tip-reference" title="Grenda, D. S., Murakami, M., Ghatak, J., Xia, J., Boxer, L. A., Dale, D., Dinauer, M. C., Link, D. C. <strong>Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis.</strong> Blood 110: 4179-4187, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17761833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17761833</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17761833[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/10.1182/blood-2006-11-057299" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17761833">Grenda et al. (2007)</a> concluded that ELA2-related disorders result from accumulation of misfolded mutant proteins, activation of the UPR, and cellular apoptosis, consistent with a toxic dominant-negative cell intrinsic effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17761833" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="Rosenberg, P. S., Alter, B. P., Link, D. C., Stein, S., Rodger, E., Bolyard, A. A., Aprikyan, A. A., Bonilla, M. A., Dror, Y., Kannourakis, G., Newburger, P. E., Boxer, L. A., Dale, D. C. <strong>Neutrophil elastase mutations and risk of leukaemia in severe congenital neutropenia.</strong> Brit. J. Haemat. 140: 210-213, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18028488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18028488</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18028488[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/10.1111/j.1365-2141.2007.06897.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18028488">Rosenberg et al. (2007)</a> reported that 2 of 4 SCN1 patients with the G185R mutation developed myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) by 15 years follow-up, whereas none of 7 patients with the P110L mutation or 5 patients with the S97L (<a href="#0008">130130.0008</a>) mutation had developed MDS/AML. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18028488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Germeshausen, M., Deerberg, S., Peter, Y., Reimer, C., Kratz, C. P., Ballmaier, M. <strong>The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia.</strong> Hum. Mutat. 34: 905-914, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23463630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23463630</a>] [<a href="https://doi.org/10.1002/humu.22308" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23463630">Germeshausen et al. (2013)</a> found 116 different ELANE mutations in 162 (41%) of 395 patients with congenital neutropenia and 26 mutations in 51 (55%) of 92 patients with cyclic neutropenia, including 69 novel mutations. The mutations were spread throughout the gene sequence. Cyclic neutropenia-associated mutations were predicted to be more benign than congenital neutropenia-associated mutations, but the mutation severity largely overlapped. The frequency of acquired CSF3R (<a href="/entry/138971">138971</a>) mutations, malignant transformation, and the need for hematopoietic stem cell transplantation were significantly higher in congenital neutropenia patients with ELANE mutations than in ELANE mutation-negative patients. Cellular elastase activity was reduced in neutrophils from all patients, irrespective of the mutation status. In congenital neutropenia, enzymatic activity was significantly lower in patients with ELANE mutations compared with those with wildtype ELANE. Despite differences in the spectrum of mutations, type or localization of mutation only partially determines the clinical phenotype. Thus, there were no apparent genotype/phenotype correlations. The report also indicated that specific ELANE mutations have limited predictive value for leukemogenesis; the risk for leukemia was correlated with disease severity rather than with occurrence of an ELANE mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23463630" 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>Bullous pemphigoid (BP) is an autoimmune skin disease characterized by subepidermal blisters and autoantibodies against 2 hemidesmosome-associated proteins, BP180 (COL17A1; <a href="/entry/113811">113811</a>) and BP240 (BPAG1; <a href="/entry/113810">113810</a>). The immunopathologic features of BP can be reproduced in mice by passive transfer of anti-BP180 antibodies. Lesion formation in this animal model depends on complement activation and neutrophil recruitment. <a href="#26" class="mim-tip-reference" title="Liu, Z., Shapiro, S. D., Zhou, X., Twining, S. S., Senior, R. M., Giudice, G. J., Fairley, J. A., Diaz, L. A. <strong>A critical role for neutrophil elastase in experimental bullous pemphigoid.</strong> J. Clin. Invest. 105: 113-123, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10619867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10619867</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10619867[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/JCI3693" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10619867">Liu et al. (2000)</a> investigated the role of neutrophil elastase in antibody-induced blister formation in experimental BP. Abnormally high levels of caseinolytic activity, consistent with NE, were detected in extracts of lesional skin and blister fluid of mice injected with anti-BP180 IgG. In NE-null (NE -/-) mutant mice, the pathogenic anti-BP180 IgG failed to induce subepidermal blistering. Wildtype mice given NE inhibitors, but not mice given cathepsin G/chymase inhibitors, were resistant to the pathogenic activity of anti-BP180 antibodies. Incubation of murine skin with NE induced BP-like epidermal-dermal detachment. Finally, <a href="#26" class="mim-tip-reference" title="Liu, Z., Shapiro, S. D., Zhou, X., Twining, S. S., Senior, R. M., Giudice, G. J., Fairley, J. A., Diaz, L. A. <strong>A critical role for neutrophil elastase in experimental bullous pemphigoid.</strong> J. Clin. Invest. 105: 113-123, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10619867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10619867</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10619867[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/JCI3693" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10619867">Liu et al. (2000)</a> showed that NE cleaved BP180 in vitro and in vivo. These results implicated NE directly in the dermal-epidermal cleavage induced by anti-BP180 antibodies in the experimental BP model. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10619867" 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 mice deficient in Ctsg and/or Ela2, <a href="#31" class="mim-tip-reference" title="Reeves, E. P., Lu, H., Jacobs, H. L., Messina, C. G. M., Bolsover, S., Gabella, G., Potma, E. O., Warley, A., Roes, J., Segal, A. W. <strong>Killing activity of neutrophils is mediated through activation of proteases by K+ flux.</strong> Nature 416: 291-297, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11907569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11907569</a>] [<a href="https://doi.org/10.1038/416291a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11907569">Reeves et al. (2002)</a> confirmed data originally generated by <a href="#38" class="mim-tip-reference" title="Tkalcevic, J., Novelli, M., Phylactides, M., Iredale, J. P., Segal, A. W., Roes, J. <strong>Impaired immunity and enhanced resistance to endotoxin in the absence of neutrophil elastase and cathepsin G.</strong> Immunity 12: 201-210, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10714686/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10714686</a>] [<a href="https://doi.org/10.1016/s1074-7613(00)80173-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10714686">Tkalcevic et al. (2000)</a> and <a href="#6" class="mim-tip-reference" title="Belaaouaj, A., McCarthy, R., Baumann, M., Gao, Z., Ley, T. J., Abraham, S. N., Shapiro, S. D. <strong>Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis.</strong> Nature Med. 4: 615-618, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9585238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9585238</a>] [<a href="https://doi.org/10.1038/nm0598-615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9585238">Belaaouaj et al. (1998)</a> that Ctsg -/- mice resist Candida but not Staphylococcal infection, whereas the reverse is true in Ela2 -/- mice. Both organisms were more virulent in double-knockout mice. Purified neutrophils from these mice mirrored these results in vitro in spite of exhibiting normal phagocytosis, degranulation, oxidase activity, superoxide production, and myeloperoxidase (MPO; <a href="/entry/606989">606989</a>) activity. <a href="#31" class="mim-tip-reference" title="Reeves, E. P., Lu, H., Jacobs, H. L., Messina, C. G. M., Bolsover, S., Gabella, G., Potma, E. O., Warley, A., Roes, J., Segal, A. W. <strong>Killing activity of neutrophils is mediated through activation of proteases by K+ flux.</strong> Nature 416: 291-297, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11907569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11907569</a>] [<a href="https://doi.org/10.1038/416291a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11907569">Reeves et al. (2002)</a> hypothesized that reactive oxygen species (ROS) and proteases act together since deficiencies in either lead to comparable reductions in killing efficiency. They determined that conditions in the phagocytic vacuole after activation provoke the influx of enormous concentrations of ROS compensated by a surge of K+ ions crossing the membrane in a pH-dependent manner. The resulting rise in ionic strength induces the release of cationic granule proteins, including Ctsg and Ela2, from the highly charged anionic sulfated proteoglycan matrix within the granules. <a href="#31" class="mim-tip-reference" title="Reeves, E. P., Lu, H., Jacobs, H. L., Messina, C. G. M., Bolsover, S., Gabella, G., Potma, E. O., Warley, A., Roes, J., Segal, A. W. <strong>Killing activity of neutrophils is mediated through activation of proteases by K+ flux.</strong> Nature 416: 291-297, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11907569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11907569</a>] [<a href="https://doi.org/10.1038/416291a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11907569">Reeves et al. (2002)</a> concluded that it is essential for the volume of the vacuole to be restricted for the requisite hypertonicity to develop. They proposed that disruption of the integrity of the cytoskeletal network by microbial products could offer a mechanism of virulence by inhibiting the activation of granule proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9585238+10714686+11907569" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Benson, K. F., Li, F.-Q., Person, R. E., Albani, D., Duan, Z., Wechsler, J., Meade-White, K., Williams, K., Acland, G. M., Niemeyer, G., Lothrop, C. D., Horwitz, M. <strong>Mutations associated with neutropenia in dogs and humans disrupt intracellular transport of neutrophil elastase.</strong> Nature Genet. 35: 90-96, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12897784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12897784</a>] [<a href="https://doi.org/10.1038/ng1224" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12897784">Benson et al. (2003)</a> stated that over 20 different mutations of neutrophil elastase had been identified, but their consequences had been elusive because they confer no consistent effects on enzymatic activity (<a href="#25" class="mim-tip-reference" title="Li, F.-Q., Horwitz, M. <strong>Characterization of mutant neutrophil elastase in severe congenital neutropenia.</strong> J. Biol. Chem. 276: 14230-14241, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11278653/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11278653</a>] [<a href="https://doi.org/10.1074/jbc.M010279200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11278653">Li and Horwitz, 2001</a>). The autosomal recessive disorder canine cyclic hematopoiesis (<a href="#27" class="mim-tip-reference" title="Lothrop, C. D., Jr., Coulson, P. A., Jr., Nolan, H. L., Cole, B., Jones, J. B., Sanders, W. L. <strong>Cyclic hormonogenesis in gray collie dogs: interactions of hematopoietic and endocrine systems.</strong> Endocrinology 120: 1027-1032, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3026784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3026784</a>] [<a href="https://doi.org/10.1210/endo-120-3-1027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3026784">Lothrop et al., 1987</a>), also known as gray collie syndrome, is not caused by mutations in neutrophil elastase. <a href="#9" class="mim-tip-reference" title="Benson, K. F., Li, F.-Q., Person, R. E., Albani, D., Duan, Z., Wechsler, J., Meade-White, K., Williams, K., Acland, G. M., Niemeyer, G., Lothrop, C. D., Horwitz, M. <strong>Mutations associated with neutropenia in dogs and humans disrupt intracellular transport of neutrophil elastase.</strong> Nature Genet. 35: 90-96, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12897784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12897784</a>] [<a href="https://doi.org/10.1038/ng1224" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12897784">Benson et al. (2003)</a> showed that homozygous mutation of the gene encoding the dog adaptor protein complex-3 (AP3) beta-subunit (AP3B1; <a href="/entry/603401">603401</a>), directing trans-Golgi export of transmembrane cargo proteins to lysosomes, causes canine cyclic hematopoiesis. C-terminal processing of neutrophil elastase exposes an AP3 interaction signal responsible for redirecting neutrophil elastase trafficking from membranes to granules. Disruption of either neutrophil elastase or AP3 perturbs the intracellular trafficking of neutrophil elastase. Most mutations in ELA2 that cause human cyclic hematopoiesis prevent membrane localization of neutrophil elastase, whereas most mutations in ELA2 that cause severe congenital neutropenia (SCN) lead to exclusive membrane localization. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12897784+11278653+3026784" 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>The elastase secreted by leukocytes is a serine protease inhibitable by alpha-1-protease inhibitor (<a href="/entry/107400">107400</a>), whereas the elastase secreted by macrophages (MMP12; <a href="/entry/601046">601046</a>) is a metalloprotease not inhibitable by alpha-1-protease inhibitor (<a href="#33" class="mim-tip-reference" title="Rosenbloom, J. <strong>Elastin: relation of protein and gene structure to disease.</strong> Lab. Invest. 51: 605-623, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6150137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6150137</a>]" pmid="6150137">Rosenbloom, 1984</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6150137" 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 3 of 13 families with cyclic neutropenia (<a href="/entry/162800">162800</a>), <a href="#20" class="mim-tip-reference" title="Horwitz, M., Benson, K. F., Person, R. E., Aprikyan, A. G., Dale, D. C. <strong>Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis.</strong> Nature Genet. 23: 433-436, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10581030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10581030</a>] [<a href="https://doi.org/10.1038/70544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10581030">Horwitz et al. (1999)</a> demonstrated a G-to-A transition in the ELA2 gene at the second position in codon 191 (numbering from the first residue after the presignal peptide had been cleaved), resulting in an arg191-to-gln amino acid substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10581030" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 of 13 families with cyclic neutropenia (<a href="/entry/162800">162800</a>), <a href="#20" class="mim-tip-reference" title="Horwitz, M., Benson, K. F., Person, R. E., Aprikyan, A. G., Dale, D. C. <strong>Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis.</strong> Nature Genet. 23: 433-436, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10581030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10581030</a>] [<a href="https://doi.org/10.1038/70544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10581030">Horwitz et al. (1999)</a> found a G-to-T transversion in the ELA2 gene at the wobble position of codon 177, resulting in replacement of the normal leucine with a phenylalanine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10581030" 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> rs137854447 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854447;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/rs137854447?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=rs137854447" 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=rs137854447" 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=RCV000018224 OR RCV001794455 OR RCV002262567 OR RCV003343600" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018224, RCV001794455, RCV002262567, RCV003343600" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018224...</a>
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<p>In 1 family, <a href="#20" class="mim-tip-reference" title="Horwitz, M., Benson, K. F., Person, R. E., Aprikyan, A. G., Dale, D. C. <strong>Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis.</strong> Nature Genet. 23: 433-436, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10581030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10581030</a>] [<a href="https://doi.org/10.1038/70544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10581030">Horwitz et al. (1999)</a> demonstrated that cyclic neutropenia (<a href="/entry/162800">162800</a>) was due to a C-to-T transition in the ELA2 gene resulting in an ala32-to-val amino acid substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10581030" 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">rs1555710005 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555710005;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=rs1555710005" 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=rs1555710005" 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 of 13 families and in a sporadic new mutation case with cyclic neutropenia (<a href="/entry/162800">162800</a>), <a href="#20" class="mim-tip-reference" title="Horwitz, M., Benson, K. F., Person, R. E., Aprikyan, A. G., Dale, D. C. <strong>Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis.</strong> Nature Genet. 23: 433-436, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10581030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10581030</a>] [<a href="https://doi.org/10.1038/70544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10581030">Horwitz et al. (1999)</a> found a splice donor mutation of intron 4 of the ELA2 gene, a transition of the invariant guanine to an adenine at the +1 position. The parents were not affected and did not carry the mutation, and paternity was confirmed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10581030" 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 CYCLIC NEUTROPENIA</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">rs879253882 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879253882;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=rs879253882" 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=rs879253882" 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=RCV000018226 OR RCV000236267 OR RCV001003809 OR RCV001795382 OR RCV002464151" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018226, RCV000236267, RCV001003809, RCV001795382, RCV002464151" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018226...</a>
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<p>In 3 families with cyclic neutropenia (<a href="/entry/162800">162800</a>), <a href="#20" class="mim-tip-reference" title="Horwitz, M., Benson, K. F., Person, R. E., Aprikyan, A. G., Dale, D. C. <strong>Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis.</strong> Nature Genet. 23: 433-436, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10581030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10581030</a>] [<a href="https://doi.org/10.1038/70544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10581030">Horwitz et al. (1999)</a> noted a G-to-A transition at the +5 position of intron 4 of the ELA2 gene, where guanine is present in 84% of cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10581030" 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 NEUTROPENIA, SEVERE CONGENITAL, 1, AUTOSOMAL DOMINANT</strong>
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ELANE, PRO110LEU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137854448 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854448;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=rs137854448" 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=rs137854448" 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=RCV000018227 OR RCV000220001 OR RCV001794456 OR RCV002472319" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018227, RCV000220001, RCV001794456, RCV002472319" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018227...</a>
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<p>In 4 unrelated patients with congenital neutropenia (SCN1; <a href="/entry/202700">202700</a>), <a href="#15" class="mim-tip-reference" title="Dale, D. C., Person, R. E., Bolyard, A. A., Aprikyan, A. G., Bos, C., Bonilla, M. A., Boxer, L. A., Kannourakis, G., Zeidler, C., Welte, K., Benson, K. F., Horwitz, M. <strong>Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia.</strong> Blood 96: 2317-2322, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11001877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11001877</a>]" pmid="11001877">Dale et al. (2000)</a> found heterozygosity for a 15862C-T transition in genomic DNA causing a pro110-to-leu (P110L) amino acid substitution. One of the families had an affected mother and 2 affected sons with different fathers, supporting autosomal dominant inheritance. Another family with the P110L mutation had an affected mother and son; another family had an affected father and daughter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11001877" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="Rosenberg, P. S., Alter, B. P., Link, D. C., Stein, S., Rodger, E., Bolyard, A. A., Aprikyan, A. A., Bonilla, M. A., Dror, Y., Kannourakis, G., Newburger, P. E., Boxer, L. A., Dale, D. C. <strong>Neutrophil elastase mutations and risk of leukaemia in severe congenital neutropenia.</strong> Brit. J. Haemat. 140: 210-213, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18028488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18028488</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18028488[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/10.1111/j.1365-2141.2007.06897.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18028488">Rosenberg et al. (2007)</a> identified the P110L mutation in 7 of 82 unrelated patients with SCN1. None of the patients had developed MDS/AML at 15 years follow-up. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18028488" 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> rs387906553 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906553;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/rs387906553?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=rs387906553" 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=rs387906553" 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=RCV000018228 OR RCV003764587" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018228, RCV003764587" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018228...</a>
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<p>In 2 unrelated families, <a href="#15" class="mim-tip-reference" title="Dale, D. C., Person, R. E., Bolyard, A. A., Aprikyan, A. G., Bos, C., Bonilla, M. A., Boxer, L. A., Kannourakis, G., Zeidler, C., Welte, K., Benson, K. F., Horwitz, M. <strong>Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia.</strong> Blood 96: 2317-2322, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11001877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11001877</a>]" pmid="11001877">Dale et al. (2000)</a> found that patients with congenital neutropenia (SCN1; <a href="/entry/202700">202700</a>) were heterozygous for the same 34371G-A substitution in exon 3 of the ELA2 gene, resulting in a val72-to-met (V72M) mutation. In 1 of the families a father and daughter were affected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11001877" 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 NEUTROPENIA, SEVERE CONGENITAL, 1, AUTOSOMAL DOMINANT</strong>
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<p><a href="#1" class="mim-tip-reference" title="Ancliff, P. J., Gale, R. E., Liesner, R., Hann, I. M., Linch, D. C. <strong>Mutations in the ELA2 gene encoding neutrophil elastase are present in most patients with sporadic severe congenital neutropenia but only in some patients with the familial form of the disease.</strong> Blood 98: 2645-2650, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11675333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11675333</a>] [<a href="https://doi.org/10.1182/blood.v98.9.2645" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11675333">Ancliff et al. (2001)</a> commented on the variation in phenotype in patients with the same ELA2 mutation. They reported 2 patients with a C-to-T transition at nucleotide 4495 in exon 4 of the ELA2 gene, resulting in a ser97-to-leu (S97L) substitution. One of the patients, aged 5 years at the time of report, had severe neutropenia (SCN1; <a href="/entry/202700">202700</a>) and remained on GCSF therapy with only a modest response. The other patient, aged 13 years at the time of report, had severe neutropenia and recurrent infections until he started GCSF at the age of 4 years. He responded well and needed only a small maintenance dose. GCSF was discontinued when he was 8; he remained free of major infections and had a neutrophil count of approximately 0.5 x 10(9)/L. The authors stated that the difference may reflect the influence of other inherited modifying factors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11675333" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="Rosenberg, P. S., Alter, B. P., Link, D. C., Stein, S., Rodger, E., Bolyard, A. A., Aprikyan, A. A., Bonilla, M. A., Dror, Y., Kannourakis, G., Newburger, P. E., Boxer, L. A., Dale, D. C. <strong>Neutrophil elastase mutations and risk of leukaemia in severe congenital neutropenia.</strong> Brit. J. Haemat. 140: 210-213, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18028488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18028488</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18028488[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/10.1111/j.1365-2141.2007.06897.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18028488">Rosenberg et al. (2007)</a> identified the S97L mutation in 5 of 82 unrelated patients with SCN1. None of the patients had developed MDS/AML at 15 years follow-up. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18028488" 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> rs28931611 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28931611;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/rs28931611?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=rs28931611" 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=rs28931611" 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 child with severe congenital neutropenia (SCN1; <a href="/entry/202700">202700</a>), <a href="#1" class="mim-tip-reference" title="Ancliff, P. J., Gale, R. E., Liesner, R., Hann, I. M., Linch, D. C. <strong>Mutations in the ELA2 gene encoding neutrophil elastase are present in most patients with sporadic severe congenital neutropenia but only in some patients with the familial form of the disease.</strong> Blood 98: 2645-2650, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11675333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11675333</a>] [<a href="https://doi.org/10.1182/blood.v98.9.2645" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11675333">Ancliff et al. (2001)</a> identified heterozygosity for a 1929T-C mutation in the ELA2 gene, resulting in a cys42-to-arg (C42R) substitution. They found mosaicism for the mutation in her healthy father. Approximately half of the father's T cells carried the mutation, in contrast to less than 10% of neutrophils. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11675333" 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">rs137854449 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854449;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=rs137854449" 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=rs137854449" 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> rs267606781 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606781;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/rs267606781?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=rs267606781" 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=rs267606781" 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 patient with severe congenital neutropenia (SCN1; <a href="/entry/202700">202700</a>), <a href="#34" class="mim-tip-reference" title="Salipante, S. J., Benson, K. F., Luty, J., Hadavi, V., Kariminejad, R., Kariminejad, M. H., Rezaei, N., Horwitz, M. S. <strong>Double de novo mutations of ELA2 in cyclic and severe congenital neutropenia.</strong> Hum. Mutat. 28: 874-881, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436313</a>] [<a href="https://doi.org/10.1002/humu.20529" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17436313">Salipante et al. (2007)</a> identified 2 de novo mutations in the ELA2 gene in cis on the paternal allele. The father was unaffected, and the mutations likely arose during spermatogenesis. The mutations, which were 9 nucleotides apart in exon 3, resulted in val69-to-leu (V69L) and val72-to-leu (V72L) substitutions. Functional expression studies showed that each mutation by itself reduced proteolytic enzyme activity by slightly less than half, but together showed an additive effect with minimal remaining enzyme activity. Nuclear localization studies showed that the V72L mutant distributed to the cytoplasm, whereas the V69L mutant accumulated at the cell surface. The 2 mutations together yielded a compromise with moderate amounts in both the cytoplasm and at the cell surface, as well as some expression in the nucleus. <a href="#34" class="mim-tip-reference" title="Salipante, S. J., Benson, K. F., Luty, J., Hadavi, V., Kariminejad, R., Kariminejad, M. H., Rezaei, N., Horwitz, M. S. <strong>Double de novo mutations of ELA2 in cyclic and severe congenital neutropenia.</strong> Hum. Mutat. 28: 874-881, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436313</a>] [<a href="https://doi.org/10.1002/humu.20529" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17436313">Salipante et al. (2007)</a> concluded that the mutations result in disturbed subcellular protein trafficking. There was also some evidence for induction of the unfolded protein response. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17436313" 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 NEUTROPENIA, SEVERE CONGENITAL, 1, AUTOSOMAL DOMINANT</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000018232 OR RCV000214338 OR RCV001336413 OR RCV001851904" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018232, RCV000214338, RCV001336413, RCV001851904" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018232...</a>
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<p>In patients with severe congenital neutropenia (SCN1; <a href="/entry/202700">202700</a>), <a href="#15" class="mim-tip-reference" title="Dale, D. C., Person, R. E., Bolyard, A. A., Aprikyan, A. G., Bos, C., Bonilla, M. A., Boxer, L. A., Kannourakis, G., Zeidler, C., Welte, K., Benson, K. F., Horwitz, M. <strong>Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia.</strong> Blood 96: 2317-2322, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11001877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11001877</a>]" pmid="11001877">Dale et al. (2000)</a> and <a href="#8" class="mim-tip-reference" title="Bellanne-Chantelot, C., Clauin, S., Leblanc, T., Cassinat, B., Rodrigues-Lima, F., Beaufils, S., Vaury, C., Barkaoui, M., Fenneteau, O., Maier-Redelsperger, M., Chomienne, C., Donadieu, J. <strong>Mutations in the ELA2 gene correlate with more severe expression of neutropenia: a study of 81 patients from the French Neutropenia Register.</strong> Blood 103: 4119-4125, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14962902/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14962902</a>] [<a href="https://doi.org/10.1182/blood-2003-10-3518" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14962902">Bellanne-Chantelot et al. (2004)</a> identified a heterozygous 4924G-A transition in exon 5 of the ELA2 gene, resulting in a gly185-to-arg (G185R) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11001877+14962902" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="Rosenberg, P. S., Alter, B. P., Link, D. C., Stein, S., Rodger, E., Bolyard, A. A., Aprikyan, A. A., Bonilla, M. A., Dror, Y., Kannourakis, G., Newburger, P. E., Boxer, L. A., Dale, D. C. <strong>Neutrophil elastase mutations and risk of leukaemia in severe congenital neutropenia.</strong> Brit. J. Haemat. 140: 210-213, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18028488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18028488</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18028488[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/10.1111/j.1365-2141.2007.06897.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18028488">Rosenberg et al. (2007)</a> identified the G185R mutation in 4 of 82 unrelated patients with SCN1. Patients with the G185R mutation had a particularly severe disease course, and 2 developed MDS/AML at 10 and 15 years, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18028488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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[<a href="https://doi.org/10.1002/humu.20529" target="_blank">Full Text</a>]
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<a id="35" class="mim-anchor"></a>
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<a id="Salipante2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Salipante, S. J., Rojas, M. E. B., Korkmaz, B., Duan, Z., Wechsler, J., Benson, K. F., Person, R. E., Grimes, H. L., Horwitz, M. S.
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<strong>Contributions to neutropenia from PFAAP5 (N4BP2L2), a novel protein mediating transcriptional repressor cooperation between Gfi1 and neutrophil elastase.</strong>
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Molec. Cell. Biol. 29: 4394-4405, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19506020/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19506020</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19506020[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=19506020" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1128/MCB.00596-09" target="_blank">Full Text</a>]
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<a id="36" class="mim-anchor"></a>
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<a id="Sinha1987" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sinha, S., Watorek, W., Karr, S., Giles, J., Bode, W., Travis, J.
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<strong>Primary structure of human neutrophil elastase.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3550808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3550808</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3550808" 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.84.8.2228" target="_blank">Full Text</a>]
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<li>
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<a id="37" class="mim-anchor"></a>
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<a id="Thusberg2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Thusberg, J., Vihinen, M.
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<strong>Bioinformatic analysis of protein structure-function relationships: case study of leukocyte elastase (ELA2) missense mutations.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16986121/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16986121</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16986121" 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/humu.20407" target="_blank">Full Text</a>]
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<a id="38" class="mim-anchor"></a>
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<a id="Tkalcevic2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tkalcevic, J., Novelli, M., Phylactides, M., Iredale, J. P., Segal, A. W., Roes, J.
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<strong>Impaired immunity and enhanced resistance to endotoxin in the absence of neutrophil elastase and cathepsin G.</strong>
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Immunity 12: 201-210, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10714686/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10714686</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10714686" 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/s1074-7613(00)80173-9" target="_blank">Full Text</a>]
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<a id="39" class="mim-anchor"></a>
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<a id="Weinrauch2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Weinrauch, Y., Drujan, D., Shapiro, S. D., Weiss, J., Zychlinsky, Z.
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<strong>Neutrophil elastase targets virulence factors of enterobacteria.</strong>
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Nature 417: 91-94, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12018205/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12018205</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12018205" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/417091a" target="_blank">Full Text</a>]
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<a id="40" class="mim-anchor"></a>
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<a id="Zhu2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhu, J., Nathan, C., Jin, W., Sim, D., Ashcroft, G. S., Wahl, S. M., Lacomis, L., Erdjument-Bromage, H., Tempst, P., Wright, C. D., Ding, A.
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<strong>Conversion of proepithelin to epithelins: roles of SLPI and elastase in host defense and wound repair.</strong>
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Cell 111: 867-878, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12526812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12526812</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12526812" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(02)01141-8" target="_blank">Full Text</a>]
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<li>
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<a id="41" class="mim-anchor"></a>
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<a id="Zimmer1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zimmer, M., Medcalf, R. L., Fink, T. M., Mattmann, C., Lichter, P., Jenne, D. E.
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<strong>Three human elastase-like genes coordinately expressed in the myelomonocyte lineage are organized as a single genetic locus on 19pter.</strong>
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Proc. Nat. Acad. Sci. 89: 8215-8219, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1518849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1518849</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1518849" 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.89.17.8215" target="_blank">Full Text</a>]
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</ol>
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<br />
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div 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 : 06/25/2018
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</span>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz - updated : 5/12/2014<br>Cassandra L. Kniffin - updated : 8/6/2013<br>Cassandra L. Kniffin - updated : 3/9/2010<br>Cassandra L. Kniffin - updated : 2/11/2009<br>Cassandra L. Kniffin - updated : 5/21/2008<br>Cassandra L. Kniffin - updated : 10/18/2007<br>Cassandra L. Kniffin - updated : 12/29/2006<br>Paul J. Converse - updated : 3/14/2005<br>Stylianos E. Antonarakis - updated : 11/19/2003<br>Victor A. McKusick - updated : 8/21/2003<br>Stylianos E. Antonarakis - updated : 1/16/2003<br>Victor A. McKusick - updated : 9/27/2002<br>Ada Hamosh - updated : 5/28/2002<br>Paul J. Converse - updated : 4/9/2002<br>Victor A. McKusick - updated : 12/13/2001<br>Ada Hamosh - updated : 8/15/2000<br>Victor A. McKusick - updated : 1/24/2000<br>Victor A. McKusick - updated : 11/30/1999<br>Victor A. McKusick - updated : 2/12/1997<br>Mark H. Paalman - edited : 8/15/1996<br>Alan F. Scott - updated : 8/14/1996
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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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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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 1/5/1988
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<a id="editHistory" class="mim-anchor"></a>
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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 class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 07/19/2018
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 07/18/2018<br>mgross : 06/25/2018<br>alopez : 09/02/2016<br>mgross : 05/14/2014<br>mcolton : 5/12/2014<br>carol : 8/14/2013<br>carol : 8/13/2013<br>tpirozzi : 8/12/2013<br>ckniffin : 8/6/2013<br>alopez : 8/9/2012<br>wwang : 6/8/2011<br>wwang : 6/7/2011<br>carol : 8/13/2010<br>wwang : 3/15/2010<br>ckniffin : 3/9/2010<br>carol : 12/10/2009<br>wwang : 4/6/2009<br>ckniffin : 2/11/2009<br>mgross : 10/28/2008<br>wwang : 5/27/2008<br>ckniffin : 5/21/2008<br>wwang : 10/26/2007<br>ckniffin : 10/18/2007<br>alopez : 2/1/2007<br>alopez : 2/1/2007<br>wwang : 1/22/2007<br>ckniffin : 12/29/2006<br>mgross : 3/14/2005<br>mgross : 3/14/2005<br>terry : 11/4/2004<br>mgross : 11/19/2003<br>alopez : 9/2/2003<br>alopez : 8/22/2003<br>terry : 8/21/2003<br>tkritzer : 2/11/2003<br>mgross : 1/16/2003<br>carol : 10/1/2002<br>tkritzer : 9/27/2002<br>tkritzer : 9/27/2002<br>ckniffin : 5/29/2002<br>terry : 5/28/2002<br>alopez : 4/9/2002<br>alopez : 4/9/2002<br>carol : 4/9/2002<br>mcapotos : 12/17/2001<br>terry : 12/13/2001<br>terry : 11/14/2001<br>mcapotos : 1/22/2001<br>mcapotos : 1/12/2001<br>terry : 1/9/2001<br>alopez : 8/17/2000<br>terry : 8/15/2000<br>mcapotos : 1/28/2000<br>mcapotos : 1/28/2000<br>mcapotos : 1/24/2000<br>terry : 1/24/2000<br>alopez : 12/1/1999<br>terry : 11/30/1999<br>terry : 11/30/1999<br>dkim : 9/8/1998<br>alopez : 5/26/1998<br>mark : 4/3/1997<br>terry : 2/12/1997<br>terry : 2/7/1997<br>mark : 8/16/1996<br>mark : 8/15/1996<br>mark : 8/15/1996<br>mark : 8/15/1996<br>mark : 8/15/1996<br>terry : 8/15/1996<br>terry : 1/18/1995<br>supermim : 3/16/1992<br>supermim : 3/20/1990<br>ddp : 10/26/1989<br>root : 4/23/1988<br>marie : 3/25/1988
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</span>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 130130
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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ELASTASE, NEUTROPHIL-EXPRESSED; ELANE
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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ELASTASE 2; ELA2<br />
|
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ELASTASE, NEUTROPHIL; NE<br />
|
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HNE<br />
|
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ELASTASE, LEUKOCYTE<br />
|
|
HLE<br />
|
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MEDULLASIN<br />
|
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PROTEASE, SERINE, BONE MARROW
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: ELANE</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 191347008;
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<strong>ICD10CM:</strong> D70.4;
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<strong>ICD9CM:</strong> 288.02;
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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>
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Cytogenetic location: 19p13.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 19:852,303-856,243 </span>
|
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</em>
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</strong>
|
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</h4>
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
|
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
|
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Inheritance
|
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</th>
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="2">
|
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<span class="mim-font">
|
|
19p13.3
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
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Neutropenia, cyclic
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
162800
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
Autosomal dominant
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
3
|
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</span>
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<tr>
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<td>
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<span class="mim-font">
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Neutropenia, severe congenital 1, autosomal dominant
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<td>
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<span class="mim-font">
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202700
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<span class="mim-font">
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Autosomal dominant
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Neutrophil elastase (EC 3.4.21.37) is a serine protease of neutrophil and monocyte granules (Horwitz et al., 1999). Its key physiologic role is in innate host defense, but it can also participate in tissue remodeling and possesses secretagogue actions important to local inflammatory responses (Chua and Laurent, 2006). </p>
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</span>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Aoki (1978) purified a 31-kD serine protease from human bone marrow cell mitochondria. Both granulocytes and erythroblasts were found to contain the protease medullasin, but it was not detected in lymphocytes or thrombocytes. It was shown to be located on the inner membrane of mitochondria. Nakamura et al. (1987) reported the complete genomic sequence and deduced the amino acid sequence of the medullasin precursor. It contains 267 amino acids, including a possible leader sequence of 29 amino acids. </p><p>Fletcher et al. (1987) cloned a cDNA encoding elastase-2 from a human pancreatic cDNA library. Similarities to and differences from elastase-1 (130120) and the chymotrypsins (e.g., 118890) were described. </p><p>Kawashima et al. (1987) isolated cDNAs from a human pancreatic cDNA library, which indicated that at least 2 elastase II messages are expressed in pancreas. The 2 human elastases II have been designated IIA and IIB. There is 90% overall homology between the amino acid sequences of these 2 classes of elastase II, which is synthesized as a preproenzyme of 269 amino acids. </p><p>Sinha et al. (1987) determined the complete amino acid sequence of human neutrophil elastase. The protein consists of 218 amino acid residues, contains 2 asparagine-linked carbohydrate side chains, and is joined together by 2 disulfide bonds. There is only moderate homology with porcine pancreatic elastase (43%). Okano et al. (1987) showed that the 218-amino acid sequence of human neutrophil elastase is identical to that of medullasin. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Belaaouaj et al. (2000) determined the mechanism of neutrophil elastase-mediated killing of E. coli. They found that neutrophil elastase degraded outer membrane protein A (OmpA), localized on the surface of gram-negative bacteria. </p><p>Weinrauch et al. (2002) identified human neutrophil elastase as a key host defense protein in preventing the escape of Shigella from phagocytic vacuoles in neutrophils. Neutrophil elastase degrades Shigella virulence factors at a 1,000-fold lower concentration than that needed to degrade other bacterial proteins. In neutrophils in which neutrophil elastase is inactivated pharmacologically or genetically, Shigella escapes from phagosomes, increasing bacterial survival. Neutrophil elastase also preferentially cleaves virulence factors of Salmonella and Yersinia. Weinrauch et al. (2002) concluded that their findings established neutrophil elastase as the first neutrophil factor that targets bacterial virulence proteins. </p><p>Increased leukocyte elastase activity in mice lacking secretory leukocyte protease inhibitor (SLPI; 107285) leads to impaired wound healing due to enhanced activity of transforming growth factor-beta (190180) and perhaps additional mechanisms (Ashcroft et al., 2000). Proepithelin (PEPI; 138945), also known as progranulin, an epithelial growth factor, can be converted to epithelins (EPIs) in vivo. Zhu et al. (2002) found that PEPI and EPIs exert opposing activities. EPIs inhibited the growth of epithelial cells but induced them to secrete the neutrophil attractant interleukin-8 (IL8; 146930), while PEPI blocked neutrophil activation by tumor necrosis factor (TNF; 191160), preventing release of oxidants and proteases. SLPI and PEPI formed complexes, preventing elastase from converting PEPI to EPIs. Supplying PEPI corrected the wound-healing defect in Slpi null mice. The authors concluded that SLPI/elastase act via PEPI/EPIs to operate a switch at the interface between innate immunity and wound healing. </p><p>The fusion protein PML (102578)-RARA (180240), which is generated by the t(15;17)(q22;q11.2) translocation associated with acute promyelocytic leukemia (APL; 612376), initiates APL when expressed in the early myeloid compartment of transgenic mice. Lane and Ley (2003) found that PML-RARA was cleaved in several positions by a neutral serine protease in a human myeloid cell line; purification revealed that the protease was ELA2. Immunofluorescence localization studies suggested that cleavage of PML-RARA must have occurred within the cell, perhaps within the nucleus. The functional importance of ELA2 for APL development was assessed in Ela2-deficient mice. More than 90% of bone marrow PML-RARA-cleaving activity was lost in the absence of Ela2, and Ela2-deficient animals, but not cathepsin G (CTSG; 116830)-deficient animals, were protected from APL development. The authors determined that primary mouse and human APL cells also contained ELA2-dependent PML-RARA-cleaving activity. Lane and Ley (2003) concluded that, since ELA2 is maximally produced in promyelocytes, it may play a role in APL pathogenesis by facilitating the leukemogenic potential of PML-RARA. </p><p>Using reporter gene assays in transfected NIH3T3 mouse fibroblasts, Salipante et al. (2009) found that nuclear ELA2 potentiated transcriptional repression by GFI1 (600871). ELA2 did not function independently as a transcriptional repressor, and corepression with GFI1 did not require proteolytically active ELA2. </p><p>Using the LSL-Kras-G12D (191170.0005) model of mouse lung adenocarcinoma (211980), Houghton et al. (2010) found that mutant mice who were also Elane -/- had markedly decreased tumor burden compared to Elane +/+ mice. All LSL-Kras/Elane +/+ mice died, whereas none of the Elane -/- mice died in the study period. In vitro studies in human and mouse adenocarcinoma cells showed that neutrophil elastase directly induced tumor cell proliferation at physiologic levels by gaining access to an endosomal compartment within tumor cells, where it degraded insulin receptor substrate-1 (IRS1; 147545). Degradation of IRS1 was associated with increased interaction between PI3K (see 171834) and the potent mitogen PDGFR (173410), skewing the PI3K axis toward tumor cell proliferation. The findings identified IRS1 as a key regulator of PI3K within malignant cells. </p><p>Using yeast 2-hybrid analysis, in vitro pull-down assays, and in vivo immunoprecipitation experiments, Duan et al. (2004) demonstrated that human NOTCH2NLA (618023) interacted with NE containing a processed N terminus and an intact C terminus. The interaction was mediated by the C terminus of NE and the C-terminal 24-amino acid (C24) domain of NOTCH2NLA. NE proteolytically cleaved NOTCH2NLA within its EGF repeats in vitro and in vivo, and the C24 domain of NOTCH2NLA appeared to provide resistance to NE protease activity. In vitro analyses showed that NOTCH2NLA repressed the transcriptional activities of Notch proteins. Disease-causing NE mutants disrupted interaction of NE with NOTCH2NLA, impaired proteolysis of NOTCH2NLA and NOTCH2 (600275), and interfered with NOTCH2 signaling. </p><p><strong><em>Role in Human Immunodeficiency Virus-1 Infection</em></strong></p><p>
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Bristow et al. (1995) found that human, but not murine, epithelial and leukocyte elastase bound the fusion domain of human immunodeficiency virus (HIV)-1 gp160 and interacted with a pentapeptide representative of the HIV-1 fusion domain. HIV-1 infectivity was blocked during, but not after, the initial contact between virus and cells. Bristow et al. (1995) suggested that the elastase present on T-cell membranes participates in permissiveness of host cells to infection. </p><p>Bristow (2001) found that decreased HIV infectivity correlated significantly with decreased cell surface expression of HLE on monocytes but not lymphocytes. Decreased levels of alpha-1-antitrypsin (AAT; 107400), also known as protease inhibitor (PI), correlated with increased cell surface HLE expression and increased HIV infectivity. </p><p>Bristow et al. (2001) showed that decreased HIV viral load correlated with decreased circulating PI. Furthermore, asymptomatic patients manifested deficient levels of active PI. Bristow et al. (2001) noted that deficient levels of PI lead to degenerative lung diseases and suggested that preventing PI deficiency may prevent HIV-associated pathophysiology. </p><p>Using subclones of monocytic cell lines, Bristow et al. (2003) showed that HLE localized to the cell surface, but not granules, of HIV-1-permissive clones, and to the granules, but not the cell surface, of HIV-1-nonpermissive clones. Stimulation of nonpermissive clones with lipopolysaccharide and LBP (151990), followed by exogenous PI, induced cell surface HLE expression, resulting in susceptibility to HIV infection. PI appeared to promote HIV coreceptor colocalization with surface HLE, thus permitting HIV infectivity. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Zimmer et al. (1992) demonstrated that the genes encoding azurocidin (NAZC; 162815), proteinase-3 (PRTN3; 177020), and neutrophil elastase each have 5 exons. All 3 genes are expressed coordinately and their protein products are packaged together at high levels into azurophil granules during neutrophil differentiation. Belaaouaj et al. (1997) demonstrated that the murine homolog of human ELA2 also contains 5 exons. </p>
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</span>
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<div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Zimmer et al. (1992) showed that the NAZC, PRTN3, and ELA2 genes are within an approximately 50-kb cluster on chromosome 19pter. </p><p>By interphase studies with differentially labeled probes for fluorescence in situ hybridization, Pilat et al. (1994) demonstrated that ELA2 is in a gene cluster on 19p13.3 with azurocidin, proteinase-3, and granzyme M (600311). </p><p>By interspecific backcross analysis, Belaaouaj et al. (1997) mapped the mouse Ela2 gene to chromosome 10. </p>
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</span>
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<div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Cyclic neutropenia (162800), also known as cyclic hematopoiesis, is an autosomal dominant disorder in which blood-cell production from the bone marrow oscillates with 21-day periodicity. Circulating neutrophils vary between almost normal numbers and zero. During intervals of neutropenia, affected individuals are at risk for opportunistic infection. Monocytes, platelets, lymphocytes, and reticulocytes also cycle with the same frequency. Horwitz et al. (1999) used a genomewide screen and positional cloning to map the locus to 19p13.3. They identified 7 different single-basepair substitutions in the ELA2 gene, each on a unique haplotype, in 13 of 13 families, as well as a new mutation in a sporadic case (e.g., 130130.0001-130130.0005). Neutrophil elastase is a target for protease inhibition by alpha-1-antitrypsin (AAT; 107400), and its unopposed release destroys tissue at sites of inflammation. Horwitz et al. (1999) hypothesized that a perturbed interaction between neutrophil elastase and serpins or other substrates may regulate mechanisms governing the clock-like timing of hematopoiesis. </p><p>After mutations in the ELA2 gene were identified as the basis of autosomal dominant cyclic neutropenia, Dale et al. (2000) hypothesized that congenital neutropenia (202700) is also due to mutation in this gene. In cyclic neutropenia, the mutations appeared to cluster near the active site of the molecule, whereas the opposite face was predominantly affected by the mutations found in congenital neutropenia. Their studies revealed that 22 of 25 patients with congenital neutropenia had 18 different heterozygous mutations. All 4 patients with cyclic neutropenia and none of 3 patients with Shwachman-Diamond syndrome (260400) had mutations of the ELA2 gene. In the congenital neutropenia patients, 5 different mutations were found in families with 2 or more affected members. Three instances of father-daughter pairs, 1 mother-son pair, and 1 mother with 2 affected sons by different fathers suggested autosomal dominant inheritance. </p><p>Because all of the mutations in the ELA2 gene associated with severe congenital neutropenia had been heterozygous, Ancliff et al. (2001) conducted a study to determine whether mutations in ELA2 could account for the disease phenotype in classic autosomal recessive severe congenital neutropenia (Kostmann disease; 610738), as well as in the sporadic and autosomal dominant types. They used direct automated sequencing to study all 5 exons of ELA2 and their flanking introns in 18 patients (3 autosomal recessive, 5 autosomal dominant from 3 kindreds, and 10 sporadic). No mutations were found in the autosomal recessive families. A point mutation was identified in 1 of 3 autosomal dominant families, and a base substitution was identified in 8 of 10 patients with the sporadic form, although 1 of the 8 was shown to have a low frequency polymorphism. These results suggested that mutations in ELA2 are not responsible for classic autosomal recessive Kostmann disease, but provided further evidence for the role of ELA2 in the autosomal dominant form of severe congenital neutropenia. </p><p>Ancliff et al. (2002) described the case of a healthy father of a patient who was demonstrated to be mosaic for his daughter's cys42-to-arg ELA2 mutation (130130.0009). Semiquantitative PCR showed that approximately half of his T cells carried the mutation, in contrast to less than 10% of neutrophils. Individual hematopoietic colonies grown from peripheral blood were heterozygous for the mutation or were homozygous wildtype. The results demonstrated that precursors containing the mutation are selectively lost during myelopoiesis or fail to develop into neutrophils. Ancliff et al. (2002) stated that this was the first in vivo confirmation of the pathogenic nature of elastase mutations in humans. The normal neutrophil count in the father suggested that the mutant elastase does not have paracrine effects. </p><p>Thusberg and Vihinen (2006) reported detailed bioinformatic analyses of 32 different pathogenic missense mutations in the ELA2 gene. Using 31 different analytic methods, the authors found that different mutations resulted in diverse deleterious effects on protein structure and function, including changes in electrostatic surface potential, contacts and stability, and aggregation, among other changes. There were no obvious genotype/phenotype correlations to explain the phenotypic expression of cyclic versus congenital neutropenia. </p><p>Salipante et al. (2007) reported 2 unrelated patients with cyclic neutropenia and severe congenital neutropenia, respectively, who each had 2 de novo mutations in cis in the ELA2 gene (see, e.g., 130130.0010). In both patients, the 2 mutations were paternally derived and likely arose during spermatogenesis. Functional expression studies showed reduced proteolytic activity, evidence for induction of the unfolded protein response, and disturbed subcellular localization consistent with protein mistrafficking. </p><p>Ishikawa et al. (2008) identified heterozygous mutations in the ELA2 gene in 11 (61%) of 18 Japanese patients with severe congenital neutropenia. Five (28%) patients had SCN3 (610738) due to mutation in the HAX1 gene (605998). </p>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Grenda et al. (2007) demonstrated significant activation of the unfolded protein response (UPR) and cellular apoptosis in cells derived from patients with SCN1 and in human granulocyte precursors specifically transfected with SCN1-associated ELA2 mutations, including V72M (130130.0007), P110L (130130.0006), and G185R (130130.0011). The UPR response was assessed by increased expression of XBP1 (194355) and HSPA5 (138120). Milder effects were observed with the cyclic neutropenia-associated R191Q (130130.0001) mutation. There was no evidence for protein mistrafficking within the cell. The findings indicated that the magnitude of UPR activation and apoptosis induced by ELA2 mutations correlated with the phenotypic severity. Grenda et al. (2007) concluded that ELA2-related disorders result from accumulation of misfolded mutant proteins, activation of the UPR, and cellular apoptosis, consistent with a toxic dominant-negative cell intrinsic effect. </p><p>Rosenberg et al. (2007) reported that 2 of 4 SCN1 patients with the G185R mutation developed myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) by 15 years follow-up, whereas none of 7 patients with the P110L mutation or 5 patients with the S97L (130130.0008) mutation had developed MDS/AML. </p><p>Germeshausen et al. (2013) found 116 different ELANE mutations in 162 (41%) of 395 patients with congenital neutropenia and 26 mutations in 51 (55%) of 92 patients with cyclic neutropenia, including 69 novel mutations. The mutations were spread throughout the gene sequence. Cyclic neutropenia-associated mutations were predicted to be more benign than congenital neutropenia-associated mutations, but the mutation severity largely overlapped. The frequency of acquired CSF3R (138971) mutations, malignant transformation, and the need for hematopoietic stem cell transplantation were significantly higher in congenital neutropenia patients with ELANE mutations than in ELANE mutation-negative patients. Cellular elastase activity was reduced in neutrophils from all patients, irrespective of the mutation status. In congenital neutropenia, enzymatic activity was significantly lower in patients with ELANE mutations compared with those with wildtype ELANE. Despite differences in the spectrum of mutations, type or localization of mutation only partially determines the clinical phenotype. Thus, there were no apparent genotype/phenotype correlations. The report also indicated that specific ELANE mutations have limited predictive value for leukemogenesis; the risk for leukemia was correlated with disease severity rather than with occurrence of an ELANE mutation. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Bullous pemphigoid (BP) is an autoimmune skin disease characterized by subepidermal blisters and autoantibodies against 2 hemidesmosome-associated proteins, BP180 (COL17A1; 113811) and BP240 (BPAG1; 113810). The immunopathologic features of BP can be reproduced in mice by passive transfer of anti-BP180 antibodies. Lesion formation in this animal model depends on complement activation and neutrophil recruitment. Liu et al. (2000) investigated the role of neutrophil elastase in antibody-induced blister formation in experimental BP. Abnormally high levels of caseinolytic activity, consistent with NE, were detected in extracts of lesional skin and blister fluid of mice injected with anti-BP180 IgG. In NE-null (NE -/-) mutant mice, the pathogenic anti-BP180 IgG failed to induce subepidermal blistering. Wildtype mice given NE inhibitors, but not mice given cathepsin G/chymase inhibitors, were resistant to the pathogenic activity of anti-BP180 antibodies. Incubation of murine skin with NE induced BP-like epidermal-dermal detachment. Finally, Liu et al. (2000) showed that NE cleaved BP180 in vitro and in vivo. These results implicated NE directly in the dermal-epidermal cleavage induced by anti-BP180 antibodies in the experimental BP model. </p><p>Using mice deficient in Ctsg and/or Ela2, Reeves et al. (2002) confirmed data originally generated by Tkalcevic et al. (2000) and Belaaouaj et al. (1998) that Ctsg -/- mice resist Candida but not Staphylococcal infection, whereas the reverse is true in Ela2 -/- mice. Both organisms were more virulent in double-knockout mice. Purified neutrophils from these mice mirrored these results in vitro in spite of exhibiting normal phagocytosis, degranulation, oxidase activity, superoxide production, and myeloperoxidase (MPO; 606989) activity. Reeves et al. (2002) hypothesized that reactive oxygen species (ROS) and proteases act together since deficiencies in either lead to comparable reductions in killing efficiency. They determined that conditions in the phagocytic vacuole after activation provoke the influx of enormous concentrations of ROS compensated by a surge of K+ ions crossing the membrane in a pH-dependent manner. The resulting rise in ionic strength induces the release of cationic granule proteins, including Ctsg and Ela2, from the highly charged anionic sulfated proteoglycan matrix within the granules. Reeves et al. (2002) concluded that it is essential for the volume of the vacuole to be restricted for the requisite hypertonicity to develop. They proposed that disruption of the integrity of the cytoskeletal network by microbial products could offer a mechanism of virulence by inhibiting the activation of granule proteins. </p><p>Benson et al. (2003) stated that over 20 different mutations of neutrophil elastase had been identified, but their consequences had been elusive because they confer no consistent effects on enzymatic activity (Li and Horwitz, 2001). The autosomal recessive disorder canine cyclic hematopoiesis (Lothrop et al., 1987), also known as gray collie syndrome, is not caused by mutations in neutrophil elastase. Benson et al. (2003) showed that homozygous mutation of the gene encoding the dog adaptor protein complex-3 (AP3) beta-subunit (AP3B1; 603401), directing trans-Golgi export of transmembrane cargo proteins to lysosomes, causes canine cyclic hematopoiesis. C-terminal processing of neutrophil elastase exposes an AP3 interaction signal responsible for redirecting neutrophil elastase trafficking from membranes to granules. Disruption of either neutrophil elastase or AP3 perturbs the intracellular trafficking of neutrophil elastase. Most mutations in ELA2 that cause human cyclic hematopoiesis prevent membrane localization of neutrophil elastase, whereas most mutations in ELA2 that cause severe congenital neutropenia (SCN) lead to exclusive membrane localization. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>History</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The elastase secreted by leukocytes is a serine protease inhibitable by alpha-1-protease inhibitor (107400), whereas the elastase secreted by macrophages (MMP12; 601046) is a metalloprotease not inhibitable by alpha-1-protease inhibitor (Rosenbloom, 1984). </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>11 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 CYCLIC NEUTROPENIA</strong>
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</span>
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</h4>
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<div>
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<span class="mim-text-font">
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ELANE, ARG191GLN
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<br />
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SNP: rs137854445,
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gnomAD: rs137854445,
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ClinVar: RCV000018222, RCV000522053, RCV001794454
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 3 of 13 families with cyclic neutropenia (162800), Horwitz et al. (1999) demonstrated a G-to-A transition in the ELA2 gene at the second position in codon 191 (numbering from the first residue after the presignal peptide had been cleaved), resulting in an arg191-to-gln amino acid substitution. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 CYCLIC NEUTROPENIA</strong>
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</span>
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</h4>
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</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
ELANE, LEU177PHE
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|
<br />
|
|
|
|
SNP: rs137854446,
|
|
|
|
|
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|
|
ClinVar: RCV000018223
|
|
|
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|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 of 13 families with cyclic neutropenia (162800), Horwitz et al. (1999) found a G-to-T transversion in the ELA2 gene at the wobble position of codon 177, resulting in replacement of the normal leucine with a phenylalanine. </p>
|
|
</span>
|
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</div>
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<div>
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|
<br />
|
|
</div>
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|
</div>
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|
<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 CYCLIC NEUTROPENIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
ELANE, ALA32VAL
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<br />
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|
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SNP: rs137854447,
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|
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gnomAD: rs137854447,
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ClinVar: RCV000018224, RCV001794455, RCV002262567, RCV003343600
|
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|
|
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 1 family, Horwitz et al. (1999) demonstrated that cyclic neutropenia (162800) was due to a C-to-T transition in the ELA2 gene resulting in an ala32-to-val amino acid substitution. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 CYCLIC NEUTROPENIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ELANE, IVS4DS, G-A, +1
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|
<br />
|
|
|
|
SNP: rs1555710005,
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|
|
ClinVar: RCV000018225, RCV000229570, RCV001267759, RCV001795376, RCV003919992
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 of 13 families and in a sporadic new mutation case with cyclic neutropenia (162800), Horwitz et al. (1999) found a splice donor mutation of intron 4 of the ELA2 gene, a transition of the invariant guanine to an adenine at the +1 position. The parents were not affected and did not carry the mutation, and paternity was confirmed. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 CYCLIC NEUTROPENIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ELANE, IVS4DS, G-A, +5
|
|
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|
|
<br />
|
|
|
|
SNP: rs879253882,
|
|
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|
|
ClinVar: RCV000018226, RCV000236267, RCV001003809, RCV001795382, RCV002464151
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 families with cyclic neutropenia (162800), Horwitz et al. (1999) noted a G-to-A transition at the +5 position of intron 4 of the ELA2 gene, where guanine is present in 84% of cases. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 NEUTROPENIA, SEVERE CONGENITAL, 1, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ELANE, PRO110LEU
|
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|
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|
|
<br />
|
|
|
|
SNP: rs137854448,
|
|
|
|
|
|
|
|
ClinVar: RCV000018227, RCV000220001, RCV001794456, RCV002472319
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 unrelated patients with congenital neutropenia (SCN1; 202700), Dale et al. (2000) found heterozygosity for a 15862C-T transition in genomic DNA causing a pro110-to-leu (P110L) amino acid substitution. One of the families had an affected mother and 2 affected sons with different fathers, supporting autosomal dominant inheritance. Another family with the P110L mutation had an affected mother and son; another family had an affected father and daughter. </p><p>Rosenberg et al. (2007) identified the P110L mutation in 7 of 82 unrelated patients with SCN1. None of the patients had developed MDS/AML at 15 years follow-up. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 NEUTROPENIA, SEVERE CONGENITAL, 1, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ELANE, VAL72MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906553,
|
|
|
|
|
|
gnomAD: rs387906553,
|
|
|
|
|
|
ClinVar: RCV000018228, RCV003764587
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated families, Dale et al. (2000) found that patients with congenital neutropenia (SCN1; 202700) were heterozygous for the same 34371G-A substitution in exon 3 of the ELA2 gene, resulting in a val72-to-met (V72M) mutation. In 1 of the families a father and daughter were affected. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 NEUTROPENIA, SEVERE CONGENITAL, 1, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ELANE, SER97LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137854450,
|
|
|
|
|
|
|
|
ClinVar: RCV000018229, RCV000508432, RCV000990116, RCV001794457, RCV004752711
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Ancliff et al. (2001) commented on the variation in phenotype in patients with the same ELA2 mutation. They reported 2 patients with a C-to-T transition at nucleotide 4495 in exon 4 of the ELA2 gene, resulting in a ser97-to-leu (S97L) substitution. One of the patients, aged 5 years at the time of report, had severe neutropenia (SCN1; 202700) and remained on GCSF therapy with only a modest response. The other patient, aged 13 years at the time of report, had severe neutropenia and recurrent infections until he started GCSF at the age of 4 years. He responded well and needed only a small maintenance dose. GCSF was discontinued when he was 8; he remained free of major infections and had a neutrophil count of approximately 0.5 x 10(9)/L. The authors stated that the difference may reflect the influence of other inherited modifying factors. </p><p>Rosenberg et al. (2007) identified the S97L mutation in 5 of 82 unrelated patients with SCN1. None of the patients had developed MDS/AML at 15 years follow-up. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 NEUTROPENIA, SEVERE CONGENITAL, 1, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ELANE, CYS42ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28931611,
|
|
|
|
|
|
gnomAD: rs28931611,
|
|
|
|
|
|
ClinVar: RCV000018230, RCV002472320
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a child with severe congenital neutropenia (SCN1; 202700), Ancliff et al. (2001) identified heterozygosity for a 1929T-C mutation in the ELA2 gene, resulting in a cys42-to-arg (C42R) substitution. They found mosaicism for the mutation in her healthy father. Approximately half of the father's T cells carried the mutation, in contrast to less than 10% of neutrophils. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 NEUTROPENIA, SEVERE CONGENITAL, 1, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ELANE, VAL69LEU AND VAL72LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137854449, rs267606781,
|
|
|
|
|
|
gnomAD: rs267606781,
|
|
|
|
|
|
ClinVar: RCV000018231
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with severe congenital neutropenia (SCN1; 202700), Salipante et al. (2007) identified 2 de novo mutations in the ELA2 gene in cis on the paternal allele. The father was unaffected, and the mutations likely arose during spermatogenesis. The mutations, which were 9 nucleotides apart in exon 3, resulted in val69-to-leu (V69L) and val72-to-leu (V72L) substitutions. Functional expression studies showed that each mutation by itself reduced proteolytic enzyme activity by slightly less than half, but together showed an additive effect with minimal remaining enzyme activity. Nuclear localization studies showed that the V72L mutant distributed to the cytoplasm, whereas the V69L mutant accumulated at the cell surface. The 2 mutations together yielded a compromise with moderate amounts in both the cytoplasm and at the cell surface, as well as some expression in the nucleus. Salipante et al. (2007) concluded that the mutations result in disturbed subcellular protein trafficking. There was also some evidence for induction of the unfolded protein response. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 NEUTROPENIA, SEVERE CONGENITAL, 1, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ELANE, GLY185ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137854451,
|
|
|
|
|
|
|
|
ClinVar: RCV000018232, RCV000214338, RCV001336413, RCV001851904
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In patients with severe congenital neutropenia (SCN1; 202700), Dale et al. (2000) and Bellanne-Chantelot et al. (2004) identified a heterozygous 4924G-A transition in exon 5 of the ELA2 gene, resulting in a gly185-to-arg (G185R) substitution. </p><p>Rosenberg et al. (2007) identified the G185R mutation in 4 of 82 unrelated patients with SCN1. Patients with the G185R mutation had a particularly severe disease course, and 2 developed MDS/AML at 10 and 15 years, respectively. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ancliff, P. J., Gale, R. E., Liesner, R., Hann, I. M., Linch, D. C.
|
|
<strong>Mutations in the ELA2 gene encoding neutrophil elastase are present in most patients with sporadic severe congenital neutropenia but only in some patients with the familial form of the disease.</strong>
|
|
Blood 98: 2645-2650, 2001.
|
|
|
|
|
|
[PubMed: 11675333]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1182/blood.v98.9.2645]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ancliff, P. J., Gale, R. E., Watts, M. J., Liesner, R., Hann, I. M., Strobel, S., Linch, D. C.
|
|
<strong>Paternal mosaicism proves the pathogenic nature of mutations in neutrophil elastase in severe congenital neutropenia.</strong>
|
|
Blood 100: 707-709, 2002.
|
|
|
|
|
|
[PubMed: 12091371]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1182/blood-2002-01-0060]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Aoki, Y.
|
|
<strong>Crystallization and characterization of a new protease in mitochondria of bone marrow cells.</strong>
|
|
J. Biol. Chem. 253: 2026-2032, 1978.
|
|
|
|
|
|
[PubMed: 632253]
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|
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|
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|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ashcroft, G. S., Lei, K., Jin, W., Longenecker, G., Kulkarni, A. B., Greenwell-Wild, T., Hale-Donze, H., McGrady, G., Song, X.-Y., Wahl, S. M.
|
|
<strong>Secretory leukocyte protease inhibitor mediates non-redundant functions necessary for normal wound healing.</strong>
|
|
Nature Med. 6: 1147-1153, 2000.
|
|
|
|
|
|
[PubMed: 11017147]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/80489]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Belaaouaj, A., Kim, K. S., Shapiro, S. D.
|
|
<strong>Degradation of outer membrane protein A in Escherichia coli killing by neutrophil elastase.</strong>
|
|
Science 289: 1185-1187, 2000.
|
|
|
|
|
|
[PubMed: 10947984]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.289.5482.1185]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Belaaouaj, A., McCarthy, R., Baumann, M., Gao, Z., Ley, T. J., Abraham, S. N., Shapiro, S. D.
|
|
<strong>Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis.</strong>
|
|
Nature Med. 4: 615-618, 1998.
|
|
|
|
|
|
[PubMed: 9585238]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nm0598-615]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Belaaouaj, A., Walsh, B. C., Jenkins, N. A., Copeland, N. G., Shapiro, S. D.
|
|
<strong>Characterization of the mouse neutrophil elastase gene and localization to chromosome 10.</strong>
|
|
Mammalian Genome 8: 5-8, 1997.
|
|
|
|
|
|
[PubMed: 9021140]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s003359900337]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bellanne-Chantelot, C., Clauin, S., Leblanc, T., Cassinat, B., Rodrigues-Lima, F., Beaufils, S., Vaury, C., Barkaoui, M., Fenneteau, O., Maier-Redelsperger, M., Chomienne, C., Donadieu, J.
|
|
<strong>Mutations in the ELA2 gene correlate with more severe expression of neutropenia: a study of 81 patients from the French Neutropenia Register.</strong>
|
|
Blood 103: 4119-4125, 2004.
|
|
|
|
|
|
[PubMed: 14962902]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1182/blood-2003-10-3518]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
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<span class="text-nowrap mim-text-font">
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Bao Lige - updated : 06/25/2018<br>Patricia A. Hartz - updated : 5/12/2014<br>Cassandra L. Kniffin - updated : 8/6/2013<br>Cassandra L. Kniffin - updated : 3/9/2010<br>Cassandra L. Kniffin - updated : 2/11/2009<br>Cassandra L. Kniffin - updated : 5/21/2008<br>Cassandra L. Kniffin - updated : 10/18/2007<br>Cassandra L. Kniffin - updated : 12/29/2006<br>Paul J. Converse - updated : 3/14/2005<br>Stylianos E. Antonarakis - updated : 11/19/2003<br>Victor A. McKusick - updated : 8/21/2003<br>Stylianos E. Antonarakis - updated : 1/16/2003<br>Victor A. McKusick - updated : 9/27/2002<br>Ada Hamosh - updated : 5/28/2002<br>Paul J. Converse - updated : 4/9/2002<br>Victor A. McKusick - updated : 12/13/2001<br>Ada Hamosh - updated : 8/15/2000<br>Victor A. McKusick - updated : 1/24/2000<br>Victor A. McKusick - updated : 11/30/1999<br>Victor A. McKusick - updated : 2/12/1997<br>Mark H. Paalman - edited : 8/15/1996<br>Alan F. Scott - updated : 8/14/1996
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Victor A. McKusick : 1/5/1988
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carol : 07/19/2018<br>carol : 07/18/2018<br>mgross : 06/25/2018<br>alopez : 09/02/2016<br>mgross : 05/14/2014<br>mcolton : 5/12/2014<br>carol : 8/14/2013<br>carol : 8/13/2013<br>tpirozzi : 8/12/2013<br>ckniffin : 8/6/2013<br>alopez : 8/9/2012<br>wwang : 6/8/2011<br>wwang : 6/7/2011<br>carol : 8/13/2010<br>wwang : 3/15/2010<br>ckniffin : 3/9/2010<br>carol : 12/10/2009<br>wwang : 4/6/2009<br>ckniffin : 2/11/2009<br>mgross : 10/28/2008<br>wwang : 5/27/2008<br>ckniffin : 5/21/2008<br>wwang : 10/26/2007<br>ckniffin : 10/18/2007<br>alopez : 2/1/2007<br>alopez : 2/1/2007<br>wwang : 1/22/2007<br>ckniffin : 12/29/2006<br>mgross : 3/14/2005<br>mgross : 3/14/2005<br>terry : 11/4/2004<br>mgross : 11/19/2003<br>alopez : 9/2/2003<br>alopez : 8/22/2003<br>terry : 8/21/2003<br>tkritzer : 2/11/2003<br>mgross : 1/16/2003<br>carol : 10/1/2002<br>tkritzer : 9/27/2002<br>tkritzer : 9/27/2002<br>ckniffin : 5/29/2002<br>terry : 5/28/2002<br>alopez : 4/9/2002<br>alopez : 4/9/2002<br>carol : 4/9/2002<br>mcapotos : 12/17/2001<br>terry : 12/13/2001<br>terry : 11/14/2001<br>mcapotos : 1/22/2001<br>mcapotos : 1/12/2001<br>terry : 1/9/2001<br>alopez : 8/17/2000<br>terry : 8/15/2000<br>mcapotos : 1/28/2000<br>mcapotos : 1/28/2000<br>mcapotos : 1/24/2000<br>terry : 1/24/2000<br>alopez : 12/1/1999<br>terry : 11/30/1999<br>terry : 11/30/1999<br>dkim : 9/8/1998<br>alopez : 5/26/1998<br>mark : 4/3/1997<br>terry : 2/12/1997<br>terry : 2/7/1997<br>mark : 8/16/1996<br>mark : 8/15/1996<br>mark : 8/15/1996<br>mark : 8/15/1996<br>mark : 8/15/1996<br>terry : 8/15/1996<br>terry : 1/18/1995<br>supermim : 3/16/1992<br>supermim : 3/20/1990<br>ddp : 10/26/1989<br>root : 4/23/1988<br>marie : 3/25/1988
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