3446 lines
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- *601488 - NEUTROPHIL CYTOSOLIC FACTOR 4; NCF4
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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">*601488</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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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/601488">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000100365;t=ENST00000248899" 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=4689" 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=601488" 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=ENSG00000100365;t=ENST00000248899" 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_000631,NM_013416,XM_047441384,XM_047441385" 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_000631" 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=601488" 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=03289&isoform_id=03289_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/NCF4" 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/458544,1765952,6729340,6729342,12803903,30583531,47519798,47678587,49457109,62898209,83699667,108884815,119580526,119580527,119580528,158255284,163644267,2217339755,2217339757,2462584922,2462584924,2462584926,2462584928,2462584930,2462584932" 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/Q15080" 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=4689" 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=ENSG00000100365;t=ENST00000248899" 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=NCF4" 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=NCF4" 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+4689" 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/NCF4" 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:4689" 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/4689" 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=chr22&hgg_gene=ENST00000248899.11&hgg_start=36861006&hgg_end=36878015&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:7662" 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://medlineplus.gov/genetics/gene/ncf4" 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=601488[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=601488[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/NCF4/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000100365" 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=NCF4" 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=NCF4" 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=NCF4" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=NCF4&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/PA31465" 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:7662" 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:109186" 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/NCF4#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:109186" 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/4689/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=4689" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-041124-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:4689" 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=NCF4&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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601488
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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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NEUTROPHIL CYTOSOLIC FACTOR 4; NCF4
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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NCF, 40-KD<br />
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p40-PHOX
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
|
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=NCF4" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">NCF4</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/22/229?start=-3&limit=10&highlight=229">22q12.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr22:36861006-36878015&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'})">22:36,861,006-36,878,015</a> </span>
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</em>
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
|
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/22/229?start=-3&limit=10&highlight=229">
|
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22q12.3
|
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</a>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
Chronic granulomatous disease 3, autosomal recessive
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/613960"> 613960 </a>
|
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|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
|
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<td>
|
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<span class="mim-font">
|
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|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/601488" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/601488" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
|
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|
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<span class="mim-font">
|
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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.">
|
|
<strong>TEXT</strong>
|
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</span>
|
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</span>
|
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</h4>
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<div>
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<p>The NCF4 gene encodes the p40-phox subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, a multicomponent enzyme system responsible for the oxidative burst in which electrons are transported from NADPH to molecular oxygen, generating reactive oxidant intermediates (summary by <a href="#12" class="mim-tip-reference" title="Zhan, S., Vazquez, N., Zhan, S., Wientjes, F. B., Budarf, M. L., Schrock, E., Ried, T., Green, E. D., Chanock, S. J. <strong>Genomic structure, chromosomal localization, start of transcription, and tissue expression of the human p40-phox, a new component of the nicotinamide adenine dinucleotide phosphate-oxidase complex.</strong> Blood 88: 2714-2721, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8839867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8839867</a>]" pmid="8839867">Zhan et al., 1996</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8839867" 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="#11" class="mim-tip-reference" title="Wientjes, F. B., Hsuan, J. J., Totty, N. F., Segal, A. W. <strong>p40(phox), a third cytosolic component of the activation complex of the NADPH oxidase to contain src homology 3 domains.</strong> Biochem. J. 296: 557-561, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8280052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8280052</a>] [<a href="https://doi.org/10.1042/bj2960557" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8280052">Wientjes et al. (1993)</a> cloned the NCF4 gene, which encodes a predicted 339-amino acid protein with a calculated molecular mass of 37 kD. The NCF4 protein has a C-terminal SH3 domain and a large region of sequence similarity with the N-terminus of p47-phox. Immunohistochemical studies showed that the NCF4 protein forms an activation complex with p47-phox (NCF1; <a href="/entry/608512">608512</a>) and p67-phox (NCF2; <a href="/entry/608515">608515</a>) with which it translocates to the membrane to associate with the flavocytochrome b. The primary association of p40-phox appeared to be with p67-phox. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8280052" 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 Northern blot analysis, <a href="#12" class="mim-tip-reference" title="Zhan, S., Vazquez, N., Zhan, S., Wientjes, F. B., Budarf, M. L., Schrock, E., Ried, T., Green, E. D., Chanock, S. J. <strong>Genomic structure, chromosomal localization, start of transcription, and tissue expression of the human p40-phox, a new component of the nicotinamide adenine dinucleotide phosphate-oxidase complex.</strong> Blood 88: 2714-2721, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8839867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8839867</a>]" pmid="8839867">Zhan et al. (1996)</a> found that expression of p40-phox mRNA was restricted to hematopoietic cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8839867" 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="#12" class="mim-tip-reference" title="Zhan, S., Vazquez, N., Zhan, S., Wientjes, F. B., Budarf, M. L., Schrock, E., Ried, T., Green, E. D., Chanock, S. J. <strong>Genomic structure, chromosomal localization, start of transcription, and tissue expression of the human p40-phox, a new component of the nicotinamide adenine dinucleotide phosphate-oxidase complex.</strong> Blood 88: 2714-2721, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8839867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8839867</a>]" pmid="8839867">Zhan et al. (1996)</a> determined that the NCF4 gene contains 10 exons spanning approximately 18 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8839867" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By FISH studies and PCR analysis of a somatic cell hybrid mapping panel, <a href="#12" class="mim-tip-reference" title="Zhan, S., Vazquez, N., Zhan, S., Wientjes, F. B., Budarf, M. L., Schrock, E., Ried, T., Green, E. D., Chanock, S. J. <strong>Genomic structure, chromosomal localization, start of transcription, and tissue expression of the human p40-phox, a new component of the nicotinamide adenine dinucleotide phosphate-oxidase complex.</strong> Blood 88: 2714-2721, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8839867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8839867</a>]" pmid="8839867">Zhan et al. (1996)</a> localized the NCF4 gene to chromosome 22q13.1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8839867" 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="#12" class="mim-tip-reference" title="Zhan, S., Vazquez, N., Zhan, S., Wientjes, F. B., Budarf, M. L., Schrock, E., Ried, T., Green, E. D., Chanock, S. J. <strong>Genomic structure, chromosomal localization, start of transcription, and tissue expression of the human p40-phox, a new component of the nicotinamide adenine dinucleotide phosphate-oxidase complex.</strong> Blood 88: 2714-2721, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8839867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8839867</a>]" pmid="8839867">Zhan et al. (1996)</a> noted that the NADPH oxidase is dormant in resting cells, but upon activation is assembled at the membrane. At the time of activation, the cytosolic complex associates with the membrane subunits gp91-phox (CYBB; <a href="/entry/300481">300481</a>) and p22-phox (CYBA; <a href="/entry/608508">608508</a>). They cited studies of patients with chronic granulomatous disease (see, e.g., CGD; <a href="/entry/306400">306400</a>), an inherited disorder of phagocytic cells, that have unequivocally established the importance of at least 2 cytosolic factors, p47-phox (NCF1; <a href="/entry/608512">608512</a>) and p67-phox (NCF2; <a href="/entry/608515">608515</a>). The absence of either prevents generation of superoxide by NADPH oxidase and clinically results in the CGD phenotype. The p40-phox protein is a cytosolic component of NADPH oxidase that copurifies with p67-phox. Although its function was not well defined, <a href="#12" class="mim-tip-reference" title="Zhan, S., Vazquez, N., Zhan, S., Wientjes, F. B., Budarf, M. L., Schrock, E., Ried, T., Green, E. D., Chanock, S. J. <strong>Genomic structure, chromosomal localization, start of transcription, and tissue expression of the human p40-phox, a new component of the nicotinamide adenine dinucleotide phosphate-oxidase complex.</strong> Blood 88: 2714-2721, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8839867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8839867</a>]" pmid="8839867">Zhan et al. (1996)</a> stated that it may be a component of the cytosolic complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8839867" 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 NCF4 gene product p40-phox stimulates phagocytosis-induced NADPH oxidase activity via the PX domain at the N terminus that binds to phosphatidylinositol 3-phosphate (PtdIns(3)P), which accumulates on phagosomes (<a href="#3" class="mim-tip-reference" title="Ellson, C. D., Gobert-Gosse, S., Anderson, K. E., Davidson, K., Erdjument-Bromage, H., Tempst, P., Thuring, J. W., Cooper, M. A., Lim, Z.-Y., Holmes, A. B., Gaffney, P. R. J., Coadwell, J., Chilvers, E. R., Hawkins, P. T., Stephens, L. R. <strong>PtdIns(3)P regulates the neutrophil oxidase complex by binding to the PX domain of p40(phox).</strong> Nature Cell Biol. 3: 679-682, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11433301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11433301</a>] [<a href="https://doi.org/10.1038/35083076" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11433301">Ellson et al., 2001</a>; <a href="#9" class="mim-tip-reference" title="Suh, C.-I., Stull, N. D., Li, X. J., Tian, W., Price, M. O., Grinstein, S., Yaffe, M. B., Atkinson, S., Dinauer, M. C. <strong>The phosphoinositide-binding protein p40(phox) activates the NADPH oxidase during Fc-gamma-IIA receptor-induced phagocytosis.</strong> J. Exp. Med. 203: 1915-1925, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16880255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16880255</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16880255[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/10.1084/jem.20052085" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16880255">Suh et al., 2006</a>; <a href="#4" class="mim-tip-reference" title="Ellson, C., Davidson, K., Anderson, K., Stephens, L. R., Hawkins, P. T. <strong>PtdIns3P binding to the PX domain of p40(phox) is a physiological signal in NADPH oxidase activation.</strong> EMBO J. 25: 4468-4478, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16990793/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16990793</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16990793[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/sj.emboj.7601346" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16990793"> Ellson et al., 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11433301+16880255+16990793" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#1" class="mim-tip-reference" title="Bravo, J., Karathanassis, D., Pacold, C. M., Pacold, M. E., Ellson, C. D., Anderson, K. E., Butler, P. J. G., Lavenir, I., Perisic, O., Hawkins, P. T., Stephens, L., Williams, R. L. <strong>The crystal structure of the PX domain from p40-phox bound to phosphatidylinositol 3-phosphate.</strong> Molec. Cell 8: 829-839, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11684018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11684018</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00372-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11684018">Bravo et al. (2001)</a> determined the 1.7-angstrom x-ray crystal structure of the phox homology (PX) domain from the p40-phox subunit of NADPH oxidase bound to PtdIns(3)P. The crystal structure showed that the PX domain embraces the 3-phosphate on 1 side of a water-filled, positively charged pocket and revealed how 3-phosphoinositide specificity is achieved. A CGD-associated mutation in the p47-phox PX domain (arg42 to gln) that abrogates PtdIns(3)P binding maps to a conserved arg in p40-phox (arg57) that does not directly interact with the phosphoinositide but instead appears to stabilize a critical lipid-binding loop. The SH3 domain present in the full-length protein does not affect soluble PtdIns(3)P binding to the p40-phox PX domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11684018" 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 immunoprecipitation analysis, <a href="#6" class="mim-tip-reference" title="Kanai, F., Liu, H., Field, S. J., Akbary, H., Matsuo, T., Brown, G. E., Cantley, L. C., Yaffe, M. B. <strong>The PX domains of p47phox and p40phox bind to lipid products of PI(3)K.</strong> Nature Cell Biol. 3: 675-678, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11433300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11433300</a>] [<a href="https://doi.org/10.1038/35083070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11433300">Kanai et al. (2001)</a> showed that mutation of arg57 in the PX domain of p40-phox or of the analogous residue, arg42, in p47-phox eliminated phosphoinositide binding. Mutation of arg90 in p47-phox markedly reduced, but did not eliminate, phosphoinositide binding. <a href="#6" class="mim-tip-reference" title="Kanai, F., Liu, H., Field, S. J., Akbary, H., Matsuo, T., Brown, G. E., Cantley, L. C., Yaffe, M. B. <strong>The PX domains of p47phox and p40phox bind to lipid products of PI(3)K.</strong> Nature Cell Biol. 3: 675-678, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11433300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11433300</a>] [<a href="https://doi.org/10.1038/35083070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11433300">Kanai et al. (2001)</a> concluded that PX domains are specific phosphoinositide-binding modules and that different PX domains have different phosphoinositide specificities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11433300" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a boy with autosomal recessive chronic granulomatous disease-3 (CGD3; <a href="/entry/613960">613960</a>), <a href="#7" class="mim-tip-reference" title="Matute, J. D., Arias, A. A., Wright, N. A. M., Wrobel, I., Waterhouse, C. C. M., Li, X. J., Marchal, C. C., Stull, N. D., Lewis, D. B., Steele, M., Kellner, J. D., Yu, W., Meroueh, S. O., Nauseef, W. M., Dinauer, M. C. <strong>A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in neutrophil NADPH oxidase activity.</strong> Blood 114: 3309-3315, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19692703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19692703</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19692703[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-2009-07-231498" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19692703">Matute et al. (2009)</a> identified compound heterozygous mutations in the NCF4 gene (10-bp dup, <a href="#0001">601488.0001</a> and R105Q, <a href="#0002">601488.0002</a>). In vitro studies of patient neutrophils showed impaired intracellular oxidant production during phagocytosis of serum opsonized S. aureus, although PMA-stimulated superoxide release was normal. The main clinical manifestation in this patient was chronic granulomatous inflammation of the gastrointestinal tract, particularly the colon and rectum, which was difficult to manage. However, he had not had infections with opportunistic pathogens characteristic of other forms of CGD. <a href="#7" class="mim-tip-reference" title="Matute, J. D., Arias, A. A., Wright, N. A. M., Wrobel, I., Waterhouse, C. C. M., Li, X. J., Marchal, C. C., Stull, N. D., Lewis, D. B., Steele, M., Kellner, J. D., Yu, W., Meroueh, S. O., Nauseef, W. M., Dinauer, M. C. <strong>A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in neutrophil NADPH oxidase activity.</strong> Blood 114: 3309-3315, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19692703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19692703</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19692703[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-2009-07-231498" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19692703">Matute et al. (2009)</a> noted that genomewide association studies (<a href="#8" class="mim-tip-reference" title="Rioux, J. D., Xavier, R. J., Taylor, K. D., Silverberg, M. S., Goyette, P., Huett, A., Green, T., Kuballa, P., Barmada, M. M., Datta, L. W., Shugart, Y. Y., Griffiths, A. M., and 13 others. <strong>Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis.</strong> Nature Genet. 39: 596-604, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17435756/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17435756</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17435756[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/ng2032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17435756">Rioux et al., 2007</a>) had identified a SNP in the NCF4 gene (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs4821544;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs4821544</a>) that was associated with Crohn disease, suggesting that there may be a relationship between NCF4, phagocytosis-induced oxidant production, and predisposition to inflammatory bowel disease (see IBD; <a href="/entry/266600">266600</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17435756+19692703" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 24 patients from 12 families of various ethnic origins with CGD3, <a href="#10" class="mim-tip-reference" title="van de Geer, A., Nieto-Patlan, A., Kuhns, D. B., Tool, A. T. J., Arias, A. A., Bouaziz, M., de Boer, M., Franco, J. L., Gazendam, R. P., van Hamme, J. L., van Houdt, M., van Leeuwen, K., and 47 others. <strong>Inherited p40-phox deficiency differs from classic chronic granulomatous disease.</strong> J. Clin. Invest. 128: 3957-3975, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29969437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29969437</a>] [<a href="https://doi.org/10.1172/JCI97116" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29969437">van de Geer et al. (2018)</a> identified homozygous or compound heterozygous mutations in the NCF4 gene (see, e.g., <a href="#0002">601488.0002</a>-<a href="#0006">601488.0006</a>). The mutations, which were found by exome sequencing or targeted panel sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. There was evidence of age-dependent or incomplete penetrance in 2 families. Mutation types included missense, nonsense, splice site, and a small in-frame deletion. They occurred throughout the gene, and the authors stated that all but 1 (R58C) were absent from the gnomAD database. In vitro functional expression studies in patient-derived cells and EBV-transformed B cells expressing the mutations showed variably impaired production of reactive oxygen species (ROS), indicating dysfunction of the NADPH oxidase complex and a loss-of-function effect. The functional impact depended on the phagocytic cell type and stimulus. Neutrophils and EBV-transformed B cells carrying the mutations showed impaired NADPH oxidase activity. Neutrophils were ineffective against Staphylococcus, had variable activity against E. coli, and retained almost normal defense against fungi. In contrast, NADPH oxidase activity in mononuclear phagocytes was similar to controls. PMA-induced DHR oxidation was normal or only mildly impaired in certain cell types and conditions, reflecting impaired, but not abolished, ROS production. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29969437" 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="#2" class="mim-tip-reference" title="Ellson, C. D., Davidson, K., Ferguson, G. J., O'Connor, R., Stephens, L. R., Hawkins, P. T. <strong>Neutrophils from p40-phox-/- mice exhibit severe defects in NADPH oxidase regulation and oxidant-dependent bacterial killing.</strong> J. Exp. Med. 203: 1927-1937, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16880254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16880254</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16880254[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/10.1084/jem.20052069" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16880254">Ellson et al. (2006)</a> generated p40-phox -/- mice, which were healthy and fertile when kept under pathogen-free barrier conditions. Neutrophils of p40-phox -/- mice showed reduced expression of p67-phox and diminished oxidase responses to a number of stimuli. Defective reactive oxygen species production by p40-phox -/- neutrophils in response to Staphylococcus aureus translated into a severe, CGD-like defect in the killing of this organism in vitro and in vivo. <a href="#2" class="mim-tip-reference" title="Ellson, C. D., Davidson, K., Ferguson, G. J., O'Connor, R., Stephens, L. R., Hawkins, P. T. <strong>Neutrophils from p40-phox-/- mice exhibit severe defects in NADPH oxidase regulation and oxidant-dependent bacterial killing.</strong> J. Exp. Med. 203: 1927-1937, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16880254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16880254</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16880254[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/10.1084/jem.20052069" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16880254">Ellson et al. (2006)</a> concluded that p40-phox is an essential component in bacterial killing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16880254" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a boy with autosomal recessive chronic granulomatous disease-3 (CGD3; <a href="/entry/613960">613960</a>), <a href="#7" class="mim-tip-reference" title="Matute, J. D., Arias, A. A., Wright, N. A. M., Wrobel, I., Waterhouse, C. C. M., Li, X. J., Marchal, C. C., Stull, N. D., Lewis, D. B., Steele, M., Kellner, J. D., Yu, W., Meroueh, S. O., Nauseef, W. M., Dinauer, M. C. <strong>A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in neutrophil NADPH oxidase activity.</strong> Blood 114: 3309-3315, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19692703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19692703</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19692703[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-2009-07-231498" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19692703">Matute et al. (2009)</a> identified compound heterozygous mutations in the NCF4 gene: a 10-bp duplication (3957_3966dupAAGGAGGATC) in exon 3, resulting in a frameshift and premature termination, and a c.6447G-A transition in exon 4, resulting in an arg105-to-gln substitution (R105Q; <a href="#0002">601488.0002</a>) in the PX domain. The frameshift predicts a truncated protein with a molecular mass of 14 kD, a truncated PX domain, and absent SH3 and PB1 domains, which may explain the reduced amount of protein detected in the patient and his carrier father. In vitro studies of patient cells showed impaired intracellular neutrophil oxidant production during phagocytosis of serum opsonized S. aureus, although PMA-stimulated superoxide release was normal. In vitro functional expression studies showed that the mutant R105Q protein remained cytosolic, did not localize to phagosomes or endosomes, and was unable to bind PtdIns(3)P in a lipid-binding assay. Moreover, the R105Q-mutant protein was unable to rescue the NADPH oxidase defect of NCF4 functionally null cells. The main clinical manifestation in this patient was chronic granulomatous inflammation of the gastrointestinal tract, particularly the colon and rectum, which was difficult to manage. However, he had not had infections with opportunistic pathogens characteristic of other forms of CGD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19692703" 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>For discussion of the c.6447G-A transition in the NCF4 gene, resulting in an arg105-to-gln (R105Q) substitution, that was found in compound heterozygous state in a boy with autosomal recessive chronic granulomatous disease-3 (CGD3; <a href="/entry/613960">613960</a>) by <a href="#7" class="mim-tip-reference" title="Matute, J. D., Arias, A. A., Wright, N. A. M., Wrobel, I., Waterhouse, C. C. M., Li, X. J., Marchal, C. C., Stull, N. D., Lewis, D. B., Steele, M., Kellner, J. D., Yu, W., Meroueh, S. O., Nauseef, W. M., Dinauer, M. C. <strong>A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in neutrophil NADPH oxidase activity.</strong> Blood 114: 3309-3315, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19692703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19692703</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19692703[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-2009-07-231498" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19692703">Matute et al. (2009)</a>, see <a href="#0001">601488.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19692703" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 6 sibs, born of consanguineous Pakistani parents (kindred B), with CGD3, <a href="#10" class="mim-tip-reference" title="van de Geer, A., Nieto-Patlan, A., Kuhns, D. B., Tool, A. T. J., Arias, A. A., Bouaziz, M., de Boer, M., Franco, J. L., Gazendam, R. P., van Hamme, J. L., van Houdt, M., van Leeuwen, K., and 47 others. <strong>Inherited p40-phox deficiency differs from classic chronic granulomatous disease.</strong> J. Clin. Invest. 128: 3957-3975, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29969437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29969437</a>] [<a href="https://doi.org/10.1172/JCI97116" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29969437">van de Geer et al. (2018)</a> identified a homozygous R105Q mutation in the NCF4 gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The affected father was also homozygous for the mutation, whereas the unaffected mother was a heterozygous carrier. In vitro studies in transfected cells showed that the mutant protein was expressed at normal levels. EBV-B cells expressing the mutation showed lack of oxygen radical production after PMA stimulation, consistent with severely impaired NADPH oxidase activity and a loss-of-function effect. Additional functional studies showed variably impaired production of reactive oxygen species depending on the cell type and stimulus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29969437" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 7/6/2020."None>Hamosh (2020)</a> noted that the R105Q variant was present at a low frequency (3.18 x 10(-5)) in only heterozygous state in the gnomAD database (July 6, 2020).</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> rs28445840 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28445840;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/rs28445840?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=rs28445840" 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=rs28445840" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 3 unrelated patients (P1, P12, and P23) with autosomal recessive chronic granulomatous disease-3 (CGD3; <a href="/entry/613960">613960</a>), <a href="#10" class="mim-tip-reference" title="van de Geer, A., Nieto-Patlan, A., Kuhns, D. B., Tool, A. T. J., Arias, A. A., Bouaziz, M., de Boer, M., Franco, J. L., Gazendam, R. P., van Hamme, J. L., van Houdt, M., van Leeuwen, K., and 47 others. <strong>Inherited p40-phox deficiency differs from classic chronic granulomatous disease.</strong> J. Clin. Invest. 128: 3957-3975, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29969437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29969437</a>] [<a href="https://doi.org/10.1172/JCI97116" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29969437">van de Geer et al. (2018)</a> identified a homozygous G-to-A transition (c.118-1G-A) in intron 2 of the NCF2 gene, resulting in a splicing defect. Analysis of patient cells showed 3 aberrantly spliced variants, all of which were predicted to result in truncated proteins. A fourth minor transcript resulted in a large in-frame deletion (c.118_198del). An asymptomatic 1-year-old sib (P13) of an affected patient (P12) was also homozygous for the mutation, suggesting incomplete or age-dependent penetrance. Two of the families were Pakistani and 1 was Russian; haplotype analysis was consistent with a founder effect. An additional patient (P11) with the disorder was found to be compound heterozygous for this splice site mutation and another splice site mutation (c.759-1G-C; <a href="#0004">601488.0004</a>). The latter mutation was predicted to result in splicing abnormalities, frameshifts, and premature termination. The mutations, which were found by whole-exome or targeted sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families; neither mutation was present in the gnomAD database. In vitro functional expression studies of the c.118_198del mutation showed that it caused a loss-of-function effect with impaired NADPH oxidase activity and decreased extracellular H2O2 production, particularly in EBV-B cells. However, there was functional variability depending on the type of phagocytic cell expressing the mutation and the stimulus presented. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29969437" 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>For discussion of the G-to-C transversion (c.759-1G-C) in intron 8 of the NCF4 gene that was found in compound heterozygous state in a patient with chronic granulomatous disease-3 (CGD3; <a href="/entry/613960">613960</a>) by <a href="#10" class="mim-tip-reference" title="van de Geer, A., Nieto-Patlan, A., Kuhns, D. B., Tool, A. T. J., Arias, A. A., Bouaziz, M., de Boer, M., Franco, J. L., Gazendam, R. P., van Hamme, J. L., van Houdt, M., van Leeuwen, K., and 47 others. <strong>Inherited p40-phox deficiency differs from classic chronic granulomatous disease.</strong> J. Clin. Invest. 128: 3957-3975, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29969437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29969437</a>] [<a href="https://doi.org/10.1172/JCI97116" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29969437">van de Geer et al. (2018)</a>, see <a href="#0003">601488.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29969437" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 sisters (P20 and P21), born of consanguineous Kuwaiti parents (kindred I), with autosomal recessive chronic granulomatous disease-3 (CGD3; <a href="/entry/613960">613960</a>), <a href="#10" class="mim-tip-reference" title="van de Geer, A., Nieto-Patlan, A., Kuhns, D. B., Tool, A. T. J., Arias, A. A., Bouaziz, M., de Boer, M., Franco, J. L., Gazendam, R. P., van Hamme, J. L., van Houdt, M., van Leeuwen, K., and 47 others. <strong>Inherited p40-phox deficiency differs from classic chronic granulomatous disease.</strong> J. Clin. Invest. 128: 3957-3975, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29969437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29969437</a>] [<a href="https://doi.org/10.1172/JCI97116" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29969437">van de Geer et al. (2018)</a> identified a homozygous c.716G-A transition in exon 8a of the NCF4 gene, resulting in a trp239-to-ter (W239X) substitution. The mutation, which was found by exome or targeted sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Western blot analysis of transfected cells showed either undetectable protein levels or very low levels of a truncated protein. Expression of the mutation into EBV-transformed B cells resulted in no detectable oxygen production after PMA stimulation, consistent with a loss-of-function effect. Additional detailed functional studies showed that the mutation caused variably impaired NADPH oxidase activity, depending on the cell type and the stimulus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29969437" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a 5-year-old girl (P14), born of consanguineous Pakistani parents, with autosomal recessive chronic granulomatous disease-3 (CGD3; <a href="/entry/613960">613960</a>), <a href="#10" class="mim-tip-reference" title="van de Geer, A., Nieto-Patlan, A., Kuhns, D. B., Tool, A. T. J., Arias, A. A., Bouaziz, M., de Boer, M., Franco, J. L., Gazendam, R. P., van Hamme, J. L., van Houdt, M., van Leeuwen, K., and 47 others. <strong>Inherited p40-phox deficiency differs from classic chronic granulomatous disease.</strong> J. Clin. Invest. 128: 3957-3975, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29969437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29969437</a>] [<a href="https://doi.org/10.1172/JCI97116" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29969437">van de Geer et al. (2018)</a> identified a homozygous T-to-G transversion in intron 1 of the NCF4 gene (c.32+2T-G). Cellular studies showed absence of the NCF4 transcript, suggesting nonsense-mediated mRNA decay and a complete loss of function. Cells carrying the mutation produced no detectable reactive oxygen species after PMA stimulation, indicating dysfunction of NADPH oxidase and a loss-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29969437" 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>REFERENCES</strong>
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[<a href="https://doi.org/10.1016/s1097-2765(01)00372-0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1084/jem.20052069" target="_blank">Full Text</a>]
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<strong>PtdIns(3)P regulates the neutrophil oxidase complex by binding to the PX domain of p40(phox).</strong>
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[<a href="https://doi.org/10.1038/35083076" target="_blank">Full Text</a>]
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Ellson, C., Davidson, K., Anderson, K., Stephens, L. R., Hawkins, P. T.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16990793/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16990793</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16990793[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=16990793" 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/sj.emboj.7601346" target="_blank">Full Text</a>]
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Hamosh, A.
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Baltimore, Md. 7/6/2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11433300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11433300</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11433300" 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/10.1038/35083070" target="_blank">Full Text</a>]
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Matute, J. D., Arias, A. A., Wright, N. A. M., Wrobel, I., Waterhouse, C. C. M., Li, X. J., Marchal, C. C., Stull, N. D., Lewis, D. B., Steele, M., Kellner, J. D., Yu, W., Meroueh, S. O., Nauseef, W. M., Dinauer, M. C.
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<strong>A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in neutrophil NADPH oxidase activity.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19692703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19692703</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19692703[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=19692703" 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/10.1182/blood-2009-07-231498" target="_blank">Full Text</a>]
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Rioux, J. D., Xavier, R. J., Taylor, K. D., Silverberg, M. S., Goyette, P., Huett, A., Green, T., Kuballa, P., Barmada, M. M., Datta, L. W., Shugart, Y. Y., Griffiths, A. M., and 13 others.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17435756/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17435756</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17435756[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=17435756" 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/ng2032" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16880255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16880255</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16880255[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=16880255" 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/10.1084/jem.20052085" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI97116" target="_blank">Full Text</a>]
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Wientjes, F. B., Hsuan, J. J., Totty, N. F., Segal, A. W.
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<strong>p40(phox), a third cytosolic component of the activation complex of the NADPH oxidase to contain src homology 3 domains.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8280052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8280052</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8280052" 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/10.1042/bj2960557" target="_blank">Full Text</a>]
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Zhan, S., Vazquez, N., Zhan, S., Wientjes, F. B., Budarf, M. L., Schrock, E., Ried, T., Green, E. D., Chanock, S. J.
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<strong>Genomic structure, chromosomal localization, start of transcription, and tissue expression of the human p40-phox, a new component of the nicotinamide adenine dinucleotide phosphate-oxidase complex.</strong>
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Blood 88: 2714-2721, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8839867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8839867</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8839867" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Paul J. Converse - updated : 8/14/2013<br>Cassandra L. Kniffin - updated : 5/12/2011<br>Paul J. Converse - updated : 2/2/2007<br>Stylianos E. Antonarakis - updated : 11/13/2001
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Victor A. McKusick : 11/7/1996
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ckniffin : 07/02/2020<br>carol : 05/27/2016<br>alopez : 9/17/2015<br>mcolton : 8/18/2015<br>carol : 9/16/2013<br>mgross : 8/14/2013<br>terry : 9/28/2011<br>terry : 6/15/2011<br>wwang : 5/31/2011<br>wwang : 5/24/2011<br>ckniffin : 5/12/2011<br>mgross : 2/2/2007<br>ckniffin : 3/12/2004<br>carol : 9/17/2003<br>mgross : 11/13/2001<br>dkim : 7/30/1998<br>jenny : 4/8/1997<br>mark : 11/7/1996<br>mark : 11/7/1996
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NEUTROPHIL CYTOSOLIC FACTOR 4; NCF4
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</span>
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</h3>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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<div>
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<h4>
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<span class="mim-font">
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NCF, 40-KD<br />
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p40-PHOX
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</span>
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</h4>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: NCF4</em></strong>
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</span>
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</p>
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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: 22q12.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 22:36,861,006-36,878,015 </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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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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22q12.3
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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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Chronic granulomatous disease 3, autosomal recessive
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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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613960
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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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>The NCF4 gene encodes the p40-phox subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, a multicomponent enzyme system responsible for the oxidative burst in which electrons are transported from NADPH to molecular oxygen, generating reactive oxidant intermediates (summary by Zhan et al., 1996). </p>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>Wientjes et al. (1993) cloned the NCF4 gene, which encodes a predicted 339-amino acid protein with a calculated molecular mass of 37 kD. The NCF4 protein has a C-terminal SH3 domain and a large region of sequence similarity with the N-terminus of p47-phox. Immunohistochemical studies showed that the NCF4 protein forms an activation complex with p47-phox (NCF1; 608512) and p67-phox (NCF2; 608515) with which it translocates to the membrane to associate with the flavocytochrome b. The primary association of p40-phox appeared to be with p67-phox. </p><p>By Northern blot analysis, Zhan et al. (1996) found that expression of p40-phox mRNA was restricted to hematopoietic cells. </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>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>Zhan et al. (1996) determined that the NCF4 gene contains 10 exons spanning approximately 18 kb. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By FISH studies and PCR analysis of a somatic cell hybrid mapping panel, Zhan et al. (1996) localized the NCF4 gene to chromosome 22q13.1. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Zhan et al. (1996) noted that the NADPH oxidase is dormant in resting cells, but upon activation is assembled at the membrane. At the time of activation, the cytosolic complex associates with the membrane subunits gp91-phox (CYBB; 300481) and p22-phox (CYBA; 608508). They cited studies of patients with chronic granulomatous disease (see, e.g., CGD; 306400), an inherited disorder of phagocytic cells, that have unequivocally established the importance of at least 2 cytosolic factors, p47-phox (NCF1; 608512) and p67-phox (NCF2; 608515). The absence of either prevents generation of superoxide by NADPH oxidase and clinically results in the CGD phenotype. The p40-phox protein is a cytosolic component of NADPH oxidase that copurifies with p67-phox. Although its function was not well defined, Zhan et al. (1996) stated that it may be a component of the cytosolic complex. </p><p>The NCF4 gene product p40-phox stimulates phagocytosis-induced NADPH oxidase activity via the PX domain at the N terminus that binds to phosphatidylinositol 3-phosphate (PtdIns(3)P), which accumulates on phagosomes (Ellson et al., 2001; Suh et al., 2006; Ellson et al., 2006). </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>Biochemical Features</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>Bravo et al. (2001) determined the 1.7-angstrom x-ray crystal structure of the phox homology (PX) domain from the p40-phox subunit of NADPH oxidase bound to PtdIns(3)P. The crystal structure showed that the PX domain embraces the 3-phosphate on 1 side of a water-filled, positively charged pocket and revealed how 3-phosphoinositide specificity is achieved. A CGD-associated mutation in the p47-phox PX domain (arg42 to gln) that abrogates PtdIns(3)P binding maps to a conserved arg in p40-phox (arg57) that does not directly interact with the phosphoinositide but instead appears to stabilize a critical lipid-binding loop. The SH3 domain present in the full-length protein does not affect soluble PtdIns(3)P binding to the p40-phox PX domain. </p><p>Using immunoprecipitation analysis, Kanai et al. (2001) showed that mutation of arg57 in the PX domain of p40-phox or of the analogous residue, arg42, in p47-phox eliminated phosphoinositide binding. Mutation of arg90 in p47-phox markedly reduced, but did not eliminate, phosphoinositide binding. Kanai et al. (2001) concluded that PX domains are specific phosphoinositide-binding modules and that different PX domains have different phosphoinositide specificities. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In a boy with autosomal recessive chronic granulomatous disease-3 (CGD3; 613960), Matute et al. (2009) identified compound heterozygous mutations in the NCF4 gene (10-bp dup, 601488.0001 and R105Q, 601488.0002). In vitro studies of patient neutrophils showed impaired intracellular oxidant production during phagocytosis of serum opsonized S. aureus, although PMA-stimulated superoxide release was normal. The main clinical manifestation in this patient was chronic granulomatous inflammation of the gastrointestinal tract, particularly the colon and rectum, which was difficult to manage. However, he had not had infections with opportunistic pathogens characteristic of other forms of CGD. Matute et al. (2009) noted that genomewide association studies (Rioux et al., 2007) had identified a SNP in the NCF4 gene (rs4821544) that was associated with Crohn disease, suggesting that there may be a relationship between NCF4, phagocytosis-induced oxidant production, and predisposition to inflammatory bowel disease (see IBD; 266600). </p><p>In 24 patients from 12 families of various ethnic origins with CGD3, van de Geer et al. (2018) identified homozygous or compound heterozygous mutations in the NCF4 gene (see, e.g., 601488.0002-601488.0006). The mutations, which were found by exome sequencing or targeted panel sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. There was evidence of age-dependent or incomplete penetrance in 2 families. Mutation types included missense, nonsense, splice site, and a small in-frame deletion. They occurred throughout the gene, and the authors stated that all but 1 (R58C) were absent from the gnomAD database. In vitro functional expression studies in patient-derived cells and EBV-transformed B cells expressing the mutations showed variably impaired production of reactive oxygen species (ROS), indicating dysfunction of the NADPH oxidase complex and a loss-of-function effect. The functional impact depended on the phagocytic cell type and stimulus. Neutrophils and EBV-transformed B cells carrying the mutations showed impaired NADPH oxidase activity. Neutrophils were ineffective against Staphylococcus, had variable activity against E. coli, and retained almost normal defense against fungi. In contrast, NADPH oxidase activity in mononuclear phagocytes was similar to controls. PMA-induced DHR oxidation was normal or only mildly impaired in certain cell types and conditions, reflecting impaired, but not abolished, ROS production. </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>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>Ellson et al. (2006) generated p40-phox -/- mice, which were healthy and fertile when kept under pathogen-free barrier conditions. Neutrophils of p40-phox -/- mice showed reduced expression of p67-phox and diminished oxidase responses to a number of stimuli. Defective reactive oxygen species production by p40-phox -/- neutrophils in response to Staphylococcus aureus translated into a severe, CGD-like defect in the killing of this organism in vitro and in vivo. Ellson et al. (2006) concluded that p40-phox is an essential component in bacterial killing. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>6 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL RECESSIVE, 3</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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NCF4, 10-BP DUP, NT3957
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<br />
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SNP: rs876657377,
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ClinVar: RCV000023112
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a boy with autosomal recessive chronic granulomatous disease-3 (CGD3; 613960), Matute et al. (2009) identified compound heterozygous mutations in the NCF4 gene: a 10-bp duplication (3957_3966dupAAGGAGGATC) in exon 3, resulting in a frameshift and premature termination, and a c.6447G-A transition in exon 4, resulting in an arg105-to-gln substitution (R105Q; 601488.0002) in the PX domain. The frameshift predicts a truncated protein with a molecular mass of 14 kD, a truncated PX domain, and absent SH3 and PB1 domains, which may explain the reduced amount of protein detected in the patient and his carrier father. In vitro studies of patient cells showed impaired intracellular neutrophil oxidant production during phagocytosis of serum opsonized S. aureus, although PMA-stimulated superoxide release was normal. In vitro functional expression studies showed that the mutant R105Q protein remained cytosolic, did not localize to phagosomes or endosomes, and was unable to bind PtdIns(3)P in a lipid-binding assay. Moreover, the R105Q-mutant protein was unable to rescue the NADPH oxidase defect of NCF4 functionally null cells. The main clinical manifestation in this patient was chronic granulomatous inflammation of the gastrointestinal tract, particularly the colon and rectum, which was difficult to manage. However, he had not had infections with opportunistic pathogens characteristic of other forms of CGD. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL RECESSIVE, 3</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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NCF4, ARG105GLN
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<br />
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SNP: rs387906808,
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gnomAD: rs387906808,
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ClinVar: RCV000023113, RCV000208606
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the c.6447G-A transition in the NCF4 gene, resulting in an arg105-to-gln (R105Q) substitution, that was found in compound heterozygous state in a boy with autosomal recessive chronic granulomatous disease-3 (CGD3; 613960) by Matute et al. (2009), see 601488.0001. </p><p>In 6 sibs, born of consanguineous Pakistani parents (kindred B), with CGD3, van de Geer et al. (2018) identified a homozygous R105Q mutation in the NCF4 gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The affected father was also homozygous for the mutation, whereas the unaffected mother was a heterozygous carrier. In vitro studies in transfected cells showed that the mutant protein was expressed at normal levels. EBV-B cells expressing the mutation showed lack of oxygen radical production after PMA stimulation, consistent with severely impaired NADPH oxidase activity and a loss-of-function effect. Additional functional studies showed variably impaired production of reactive oxygen species depending on the cell type and stimulus. </p><p>Hamosh (2020) noted that the R105Q variant was present at a low frequency (3.18 x 10(-5)) in only heterozygous state in the gnomAD database (July 6, 2020).</p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL RECESSIVE, 3</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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NCF4, IVS2AS, G-A, -1
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<br />
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SNP: rs28445840,
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gnomAD: rs28445840,
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ClinVar: RCV000488142, RCV001200053
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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 unrelated patients (P1, P12, and P23) with autosomal recessive chronic granulomatous disease-3 (CGD3; 613960), van de Geer et al. (2018) identified a homozygous G-to-A transition (c.118-1G-A) in intron 2 of the NCF2 gene, resulting in a splicing defect. Analysis of patient cells showed 3 aberrantly spliced variants, all of which were predicted to result in truncated proteins. A fourth minor transcript resulted in a large in-frame deletion (c.118_198del). An asymptomatic 1-year-old sib (P13) of an affected patient (P12) was also homozygous for the mutation, suggesting incomplete or age-dependent penetrance. Two of the families were Pakistani and 1 was Russian; haplotype analysis was consistent with a founder effect. An additional patient (P11) with the disorder was found to be compound heterozygous for this splice site mutation and another splice site mutation (c.759-1G-C; 601488.0004). The latter mutation was predicted to result in splicing abnormalities, frameshifts, and premature termination. The mutations, which were found by whole-exome or targeted sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families; neither mutation was present in the gnomAD database. In vitro functional expression studies of the c.118_198del mutation showed that it caused a loss-of-function effect with impaired NADPH oxidase activity and decreased extracellular H2O2 production, particularly in EBV-B cells. However, there was functional variability depending on the type of phagocytic cell expressing the mutation and the stimulus presented. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL RECESSIVE, 3</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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NCF4, IVS8DS, G-C, -1
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<br />
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SNP: rs200347935,
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gnomAD: rs200347935,
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ClinVar: RCV000648867, RCV004689827
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the G-to-C transversion (c.759-1G-C) in intron 8 of the NCF4 gene that was found in compound heterozygous state in a patient with chronic granulomatous disease-3 (CGD3; 613960) by van de Geer et al. (2018), see 601488.0003. </p>
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</span>
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</div>
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<strong>.0005 GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL RECESSIVE, 3</strong>
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NCF4, TRP239TER
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<br />
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SNP: rs1940176752,
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ClinVar: RCV001200054
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<p>In 2 sisters (P20 and P21), born of consanguineous Kuwaiti parents (kindred I), with autosomal recessive chronic granulomatous disease-3 (CGD3; 613960), van de Geer et al. (2018) identified a homozygous c.716G-A transition in exon 8a of the NCF4 gene, resulting in a trp239-to-ter (W239X) substitution. The mutation, which was found by exome or targeted sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Western blot analysis of transfected cells showed either undetectable protein levels or very low levels of a truncated protein. Expression of the mutation into EBV-transformed B cells resulted in no detectable oxygen production after PMA stimulation, consistent with a loss-of-function effect. Additional detailed functional studies showed that the mutation caused variably impaired NADPH oxidase activity, depending on the cell type and the stimulus. </p>
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<span class="mim-font">
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<strong>.0006 GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL RECESSIVE, 3</strong>
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<span class="mim-text-font">
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NCF4, IVS1DS, T-G, +2
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<br />
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SNP: rs1601543670,
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ClinVar: RCV001200055
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<p>In a 5-year-old girl (P14), born of consanguineous Pakistani parents, with autosomal recessive chronic granulomatous disease-3 (CGD3; 613960), van de Geer et al. (2018) identified a homozygous T-to-G transversion in intron 1 of the NCF4 gene (c.32+2T-G). Cellular studies showed absence of the NCF4 transcript, suggesting nonsense-mediated mRNA decay and a complete loss of function. Cells carrying the mutation produced no detectable reactive oxygen species after PMA stimulation, indicating dysfunction of NADPH oxidase and a loss-of-function effect. </p>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<ol>
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<li>
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<p class="mim-text-font">
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Bravo, J., Karathanassis, D., Pacold, C. M., Pacold, M. E., Ellson, C. D., Anderson, K. E., Butler, P. J. G., Lavenir, I., Perisic, O., Hawkins, P. T., Stephens, L., Williams, R. L.
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<strong>The crystal structure of the PX domain from p40-phox bound to phosphatidylinositol 3-phosphate.</strong>
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Molec. Cell 8: 829-839, 2001.
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[PubMed: 11684018]
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[Full Text: https://doi.org/10.1016/s1097-2765(01)00372-0]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Ellson, C. D., Davidson, K., Ferguson, G. J., O'Connor, R., Stephens, L. R., Hawkins, P. T.
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<strong>Neutrophils from p40-phox-/- mice exhibit severe defects in NADPH oxidase regulation and oxidant-dependent bacterial killing.</strong>
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J. Exp. Med. 203: 1927-1937, 2006.
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[PubMed: 16880254]
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[Full Text: https://doi.org/10.1084/jem.20052069]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Ellson, C. D., Gobert-Gosse, S., Anderson, K. E., Davidson, K., Erdjument-Bromage, H., Tempst, P., Thuring, J. W., Cooper, M. A., Lim, Z.-Y., Holmes, A. B., Gaffney, P. R. J., Coadwell, J., Chilvers, E. R., Hawkins, P. T., Stephens, L. R.
|
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<strong>PtdIns(3)P regulates the neutrophil oxidase complex by binding to the PX domain of p40(phox).</strong>
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Nature Cell Biol. 3: 679-682, 2001.
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[PubMed: 11433301]
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[Full Text: https://doi.org/10.1038/35083076]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Ellson, C., Davidson, K., Anderson, K., Stephens, L. R., Hawkins, P. T.
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<strong>PtdIns3P binding to the PX domain of p40(phox) is a physiological signal in NADPH oxidase activation.</strong>
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EMBO J. 25: 4468-4478, 2006.
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[PubMed: 16990793]
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[Full Text: https://doi.org/10.1038/sj.emboj.7601346]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Hamosh, A.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 7/6/2020.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Kanai, F., Liu, H., Field, S. J., Akbary, H., Matsuo, T., Brown, G. E., Cantley, L. C., Yaffe, M. B.
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<strong>The PX domains of p47phox and p40phox bind to lipid products of PI(3)K.</strong>
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Nature Cell Biol. 3: 675-678, 2001.
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[PubMed: 11433300]
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[Full Text: https://doi.org/10.1038/35083070]
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</li>
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<li>
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<p class="mim-text-font">
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Matute, J. D., Arias, A. A., Wright, N. A. M., Wrobel, I., Waterhouse, C. C. M., Li, X. J., Marchal, C. C., Stull, N. D., Lewis, D. B., Steele, M., Kellner, J. D., Yu, W., Meroueh, S. O., Nauseef, W. M., Dinauer, M. C.
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<strong>A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in neutrophil NADPH oxidase activity.</strong>
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Blood 114: 3309-3315, 2009.
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[PubMed: 19692703]
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[Full Text: https://doi.org/10.1182/blood-2009-07-231498]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Rioux, J. D., Xavier, R. J., Taylor, K. D., Silverberg, M. S., Goyette, P., Huett, A., Green, T., Kuballa, P., Barmada, M. M., Datta, L. W., Shugart, Y. Y., Griffiths, A. M., and 13 others.
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<strong>Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis.</strong>
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Nature Genet. 39: 596-604, 2007.
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[PubMed: 17435756]
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[Full Text: https://doi.org/10.1038/ng2032]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Suh, C.-I., Stull, N. D., Li, X. J., Tian, W., Price, M. O., Grinstein, S., Yaffe, M. B., Atkinson, S., Dinauer, M. C.
|
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<strong>The phosphoinositide-binding protein p40(phox) activates the NADPH oxidase during Fc-gamma-IIA receptor-induced phagocytosis.</strong>
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J. Exp. Med. 203: 1915-1925, 2006.
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[PubMed: 16880255]
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[Full Text: https://doi.org/10.1084/jem.20052085]
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</p>
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<li>
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<p class="mim-text-font">
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van de Geer, A., Nieto-Patlan, A., Kuhns, D. B., Tool, A. T. J., Arias, A. A., Bouaziz, M., de Boer, M., Franco, J. L., Gazendam, R. P., van Hamme, J. L., van Houdt, M., van Leeuwen, K., and 47 others.
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<strong>Inherited p40-phox deficiency differs from classic chronic granulomatous disease.</strong>
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J. Clin. Invest. 128: 3957-3975, 2018.
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[PubMed: 29969437]
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[Full Text: https://doi.org/10.1172/JCI97116]
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</li>
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<p class="mim-text-font">
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Wientjes, F. B., Hsuan, J. J., Totty, N. F., Segal, A. W.
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<strong>p40(phox), a third cytosolic component of the activation complex of the NADPH oxidase to contain src homology 3 domains.</strong>
|
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Biochem. J. 296: 557-561, 1993.
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[PubMed: 8280052]
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[Full Text: https://doi.org/10.1042/bj2960557]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Zhan, S., Vazquez, N., Zhan, S., Wientjes, F. B., Budarf, M. L., Schrock, E., Ried, T., Green, E. D., Chanock, S. J.
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<strong>Genomic structure, chromosomal localization, start of transcription, and tissue expression of the human p40-phox, a new component of the nicotinamide adenine dinucleotide phosphate-oxidase complex.</strong>
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Blood 88: 2714-2721, 1996.
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[PubMed: 8839867]
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Cassandra L. Kniffin - updated : 07/02/2020<br>Paul J. Converse - updated : 8/14/2013<br>Cassandra L. Kniffin - updated : 5/12/2011<br>Paul J. Converse - updated : 2/2/2007<br>Stylianos E. Antonarakis - updated : 11/13/2001
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<span class="mim-text-font">
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Victor A. McKusick : 11/7/1996
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carol : 07/06/2020<br>ckniffin : 07/02/2020<br>carol : 05/27/2016<br>alopez : 9/17/2015<br>mcolton : 8/18/2015<br>carol : 9/16/2013<br>mgross : 8/14/2013<br>terry : 9/28/2011<br>terry : 6/15/2011<br>wwang : 5/31/2011<br>wwang : 5/24/2011<br>ckniffin : 5/12/2011<br>mgross : 2/2/2007<br>ckniffin : 3/12/2004<br>carol : 9/17/2003<br>mgross : 11/13/2001<br>dkim : 7/30/1998<br>jenny : 4/8/1997<br>mark : 11/7/1996<br>mark : 11/7/1996
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