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Entry
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- *605956 - NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN PROTEIN 2; NOD2
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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">*605956</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#evolution">Evolution</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/605956">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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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=ENSG00000167207;t=ENST00000647318" 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=64127" 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=605956" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000167207;t=ENST00000647318" 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_001293557,NM_001370466,NM_022162,NR_163434,XM_006721242,XM_006721243,XM_011523260,XM_011523261,XM_017023536,XM_017023537,XM_047434452,XM_047434453,XM_047434454,XM_047434455,XM_047434456,XM_047434457,XR_007064894,XR_007064895" 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_001370466" 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=605956" 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=05810&isoform_id=05810_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/NOD2" 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/11275614,11545912,14488149,14595628,14595630,14595632,14595634,14595636,14595638,16508848,16508850,20137973,37575485,115393954,115606182,119603173,125489163,151564481,151564483,151564485,194045622,194389736,195360695,195360700,195360705,195360709,261824320,296060722,302128094,302128096,307829324,578829112,578829116,649572336,767990355,767990358,1034595528,1034595531,1486315210,1635381371,2217306942,2217306944,2217306946,2217306955,2217306957,2217306959,2462550119,2462550121,2462550123,2462550125,2462550127,2462550129,2462550131,2462550134,2462550136,2462550139,2462550141,2462550143" 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/Q9HC29" 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=64127" 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=ENSG00000167207;t=ENST00000647318" 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=NOD2" 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=NOD2" 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+64127" 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/NOD2" 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:64127" 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/64127" 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=chr16&hgg_gene=ENST00000647318.2&hgg_start=50693606&hgg_end=50733075&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:5331" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/nod2" 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=605956[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=605956[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/NOD2/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/ENSG00000167207" 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=NOD2" 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=NOD2" 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=NOD2" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://fmf.igh.cnrs.fr/infevers/" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=NOD2&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/PA26074" 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:5331" 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:2429397" 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/NOD2#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:2429397" 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/64127/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=64127" 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-061108-4" 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:64127" 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=NOD2&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 818950005<br />
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<strong>ICD10CM:</strong> M04.8<br />
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">ICD+</a>
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
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605956
|
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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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NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN PROTEIN 2; NOD2
|
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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>
|
|
</span>
|
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</p>
|
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</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
CASPASE RECRUITMENT DOMAIN-CONTAINING PROTEIN 15; CARD15
|
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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>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=NOD2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">NOD2</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>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/16/429?start=-3&limit=10&highlight=429">16q12.1</a>
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr16:50693606-50733075&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'})">16:50,693,606-50,733,075</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
|
</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=266600,617321,186580" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/16/429?start=-3&limit=10&highlight=429">
|
|
16q12.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
{Inflammatory bowel disease 1, Crohn disease}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/266600"> 266600 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Multifactorial">Mu</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
|
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<tr>
|
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<td>
|
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<span class="mim-font">
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<p>Inflammatory responses are triggered when pattern-recognition receptors (PRRs) detect tissue damage or microbial infection. NOD2 belongs to the nucleotide-binding oligomerization domain (NOD)-like receptor family of PRRs (summary by <a href="#24" class="mim-tip-reference" title="Keestra-Gounder, A. M., Byndloss, M. X., Seyffert, N., Young, B. M., Chavez-Arroyo, A., Tsai, A. Y., Cevallos, S. A., Winter, M. G., Pham, O. H., Tiffany, C. R., de Jong, M. F., Kerrinnes, T., Ravindran, R., Luciw, P. A., McSorley, S. J., Baumler, A. J., Tsolis, R. M. <strong>NOD1 and NOD2 signalling links ER stress with inflammation.</strong> Nature 532: 394-397, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27007849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27007849</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27007849[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/nature17631" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27007849">Keestra-Gounder et al., 2016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27007849" 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>APAF1 (<a href="/entry/602233">602233</a>) and NOD1 (<a href="/entry/605980">605980</a>), also called CARD4, are members of a family of intracellular proteins that contain an N-terminal caspase recruitment domain (CARD), a centrally located nucleotide-binding domain (NBD), and a C-terminal regulatory domain. In the case of APAF1, the C-terminal regulatory domain consists of WD40 repeats, whereas NOD1 has leucine-rich repeats (LRRs). NOD1 promotes apoptosis through nuclear factor kappa-B (NFKB; see <a href="/entry/164011">164011</a>) activation and has structural similarity to a class of disease-resistance genes in plants that induce localized cell death at the site of pathogen invasion. By searching a genomic database for NOD1 homologs, followed by 5-prime RACE and RT-PCR, <a href="#40" class="mim-tip-reference" title="Ogura, Y., Inohara, N., Benito, A., Chen, F. F., Yamaoka, S., Nunez, G. <strong>Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappa-B.</strong> J. Biol. Chem. 276: 4812-4818, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11087742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11087742</a>] [<a href="https://doi.org/10.1074/jbc.M008072200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11087742">Ogura et al. (2001)</a> obtained cDNAs encoding NOD2. Sequence analysis predicted that the 1,040-amino acid NOD2 protein, which is 34% identical to NOD1, contains 2 N-terminal CARDs fused to a central NBD domain followed by 10 tandem LRRs. <a href="#39" class="mim-tip-reference" title="Ogura, Y., Bonen, D. K., Inohara, N., Nicolae, D. L., Chen, F. F., Ramos, R., Britton, H., Moran, T., Karaliuskas, R., Duerr, R. H., Achkar, J.-P., Brant, S. R., Bayless, T. M., Kirschner, B. S., Hanauer, S. B., Nunez, G., Cho, J. H. <strong>A frameshift mutation in Nod2 associated with susceptibility to Crohn's disease.</strong> Nature 411: 603-606, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11385577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11385577</a>] [<a href="https://doi.org/10.1038/35079114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11385577">Ogura et al. (2001)</a> also identified a NOD2 variant encoding a 1,013-amino acid protein, which they called NOD2B. Northern blot analysis detected 7.0- and 5.5-kb NOD2 transcripts in peripheral blood leukocytes, with little or no expression found in other tissues. RT-PCR analysis revealed expression primarily in monocytes. In contrast, NOD1 and APAF1 are broadly expressed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11087742+11385577" 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 5-prime RACE and semiquantitative RT-PCR, <a href="#25" class="mim-tip-reference" title="King, K., Bagnall, R., Fisher, S. A., Sheikh, F., Cuthbert, A., Tan, S., Mundy, N. I., Rosenstiel, P., Schreiber, S., Mathew, C. G., Roberts, R. G. <strong>Identification, evolution, and association study of a novel promoter and first exon of the human NOD2 (CARD15) gene.</strong> Genomics 90: 493-501, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17719742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17719742</a>] [<a href="https://doi.org/10.1016/j.ygeno.2007.07.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17719742">King et al. (2007)</a> showed that most human NOD2 transcripts in blood leukocytes and colon are products of an alternative first exon. They concluded that the principal NOD2 protein product lacks 27 previously reported N-terminal amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17719742" 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="#25" class="mim-tip-reference" title="King, K., Bagnall, R., Fisher, S. A., Sheikh, F., Cuthbert, A., Tan, S., Mundy, N. I., Rosenstiel, P., Schreiber, S., Mathew, C. G., Roberts, R. G. <strong>Identification, evolution, and association study of a novel promoter and first exon of the human NOD2 (CARD15) gene.</strong> Genomics 90: 493-501, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17719742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17719742</a>] [<a href="https://doi.org/10.1016/j.ygeno.2007.07.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17719742">King et al. (2007)</a> identified an alternative first exon that lies within a strong CpG island about 3.5 kb upstream of the canonical first exon of the NOD2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17719742" 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 analysis of BAC clones, <a href="#40" class="mim-tip-reference" title="Ogura, Y., Inohara, N., Benito, A., Chen, F. F., Yamaoka, S., Nunez, G. <strong>Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappa-B.</strong> J. Biol. Chem. 276: 4812-4818, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11087742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11087742</a>] [<a href="https://doi.org/10.1074/jbc.M008072200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11087742">Ogura et al. (2001)</a> determined that the NOD2 gene maps to 16q12 and contains 12 coding exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11087742" 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="#40" class="mim-tip-reference" title="Ogura, Y., Inohara, N., Benito, A., Chen, F. F., Yamaoka, S., Nunez, G. <strong>Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappa-B.</strong> J. Biol. Chem. 276: 4812-4818, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11087742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11087742</a>] [<a href="https://doi.org/10.1074/jbc.M008072200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11087742">Ogura et al. (2001)</a> found that expression of NOD2 or NOD2B resulted in NFKB activation and that mutants lacking the LRRs had enhanced NFKB activation. They determined that both intact CARD domains were necessary and sufficient for IKK-gamma (IKBKG; <a href="/entry/300248">300248</a>)- and RICK (RIPK2; <a href="/entry/603455">603455</a>)-dependent NFKB activation. Coimmunoprecipitation analysis showed that the CARD domain of RICK interacted with the CARD domains of NOD2. <a href="#40" class="mim-tip-reference" title="Ogura, Y., Inohara, N., Benito, A., Chen, F. F., Yamaoka, S., Nunez, G. <strong>Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappa-B.</strong> J. Biol. Chem. 276: 4812-4818, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11087742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11087742</a>] [<a href="https://doi.org/10.1074/jbc.M008072200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11087742">Ogura et al. (2001)</a> proposed that NOD2 serves as an intracellular receptor for bacterial products in monocytes and transduces signals leading to NFKB activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11087742" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Cooney, R., Baker, J., Brain, O., Danis, B., Pichulik, T., Allan, P., Ferguson, D. J. P., Campbell, B. J., Jewell, D., Simmons, A. <strong>NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation.</strong> Nature Med. 16: 90-97, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19966812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19966812</a>] [<a href="https://doi.org/10.1038/nm.2069" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19966812">Cooney et al. (2010)</a> showed that activation of NOD2 with muramyldipeptide induced autophagy in dendritic cells (DCs) that required RIPK2, PI3K (see <a href="/entry/601232">601232</a>), ATG5 (<a href="/entry/604261">604261</a>), ATG7 (<a href="/entry/608760">608760</a>), and ATG16L1 (<a href="/entry/610767">610767</a>), but not NALP3 (NLRP3; <a href="/entry/606416">606416</a>). DCs from Crohn disease (CD; <a href="/entry/266600">266600</a>) patients with susceptibility variants in NOD2 (e.g., 1007fs; <a href="#0001">605956.0001</a>) or ATG16L1 (T300A; <a href="/entry/610767#0001">610767.0001</a>) were deficient in autophagy induction. DCs from CD patients with NOD2 variants also showed reduced localization of bacteria in autophagolysosomes, which could be reversed by treatment with rapamycin. <a href="#6" class="mim-tip-reference" title="Cooney, R., Baker, J., Brain, O., Danis, B., Pichulik, T., Allan, P., Ferguson, D. J. P., Campbell, B. J., Jewell, D., Simmons, A. <strong>NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation.</strong> Nature Med. 16: 90-97, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19966812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19966812</a>] [<a href="https://doi.org/10.1038/nm.2069" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19966812">Cooney et al. (2010)</a> concluded that NOD2 influences bacterial degradation and interacts with the major histocompatibility complex class II antigen presentation machinery within DCs, and that ATG16L1 and NOD2 are linked within 1 functional pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19966812" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Brain, O., Owens, B. M. J., Pichulik, T., Allan, P., Khatamzas, E., Leslie, A., Steevels, T., Sharma, S., Mayer, A., Catuneanu, A. M., Morton, V., Sun, M.-Y., Jewell, D., Coccia, M., Harrison, O., Maloy, K., Schonefeldt, S., Bornschein, S., Liston, A., Simmons, A. <strong>The intracellular sensor NOD2 induces microRNA-29 expression in human dendritic cells to limit IL-23 release.</strong> Immunity 39: 521-536, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24054330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24054330</a>] [<a href="https://doi.org/10.1016/j.immuni.2013.08.035" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24054330">Brain et al. (2013)</a> detected upregulated expression of MIR29A (<a href="/entry/610782">610782</a>), MIR29B (see <a href="/entry/610783">610783</a>), and MIR29C (<a href="/entry/610784">610784</a>) in human DCs stimulated with NOD2. They found that MIR29 regulated expression of multiple immune mediators. Notably, MIR29 downregulated IL23 by targeting its IL12p40 component directly and its IL23p19 (IL23A; <a href="/entry/605580">605580</a>) component indirectly, most likely through a reduction of the transcription factor ATF2 (<a href="/entry/123811">123811</a>). Dextran sodium sulfate (DSS)-induced colitis was exacerbated in mice lacking Mir29 and was associated with elevated Il23 and Th17 cytokines in intestinal mucosa. DCs from Crohn disease patients expressing NOD2 polymorphisms failed to induce MIR29 after stimulation of pathogen pattern recognition receptors, and these DCs showed enhanced release of IL12p40 on exposure to adherent E. coli. <a href="#2" class="mim-tip-reference" title="Brain, O., Owens, B. M. J., Pichulik, T., Allan, P., Khatamzas, E., Leslie, A., Steevels, T., Sharma, S., Mayer, A., Catuneanu, A. M., Morton, V., Sun, M.-Y., Jewell, D., Coccia, M., Harrison, O., Maloy, K., Schonefeldt, S., Bornschein, S., Liston, A., Simmons, A. <strong>The intracellular sensor NOD2 induces microRNA-29 expression in human dendritic cells to limit IL-23 release.</strong> Immunity 39: 521-536, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24054330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24054330</a>] [<a href="https://doi.org/10.1016/j.immuni.2013.08.035" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24054330">Brain et al. (2013)</a> proposed that loss of MIR29-mediated immune regulation in Crohn disease DCs may contribute to elevated IL23 in patients with the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24054330" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="Nakamura, N., Lill, J. R., Phung, Q., Jiang, Z., Bakalarski, C., de Maziere, A., Klumperman, J., Schlatter, M., Delamarre, L., Mellman, I. <strong>Endosomes are specialized platforms for bacterial sensing and NOD2 signalling.</strong> Nature 509: 240-244, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24695226/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24695226</a>] [<a href="https://doi.org/10.1038/nature13133" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24695226">Nakamura et al. (2014)</a> showed that 2 endolysosomal peptide transporters, SLC15A3 (<a href="/entry/610408">610408</a>) and SLC15A4 (<a href="/entry/615806">615806</a>), are preferentially expressed by dendritic cells, especially after Toll-like receptor (TLR) stimulation. The transporters mediate the egress of bacterially derived components, such as the NOD2 cognate ligand muramyl dipeptide (MDP), and are selectively required for NOD2 responses to endosomally derived MDP. Enhanced expression of the transporters also generates endosomal membrane tubules characteristic of dendritic cells, which further enhanced the NOD2-dependent response to MDP. Finally, sensing required the recruitment of NOD2 and its effector kinase RIPK2 to the endosomal membrane, possibly by forming a complex with SLC15A3 or SLC15A4. Thus, <a href="#37" class="mim-tip-reference" title="Nakamura, N., Lill, J. R., Phung, Q., Jiang, Z., Bakalarski, C., de Maziere, A., Klumperman, J., Schlatter, M., Delamarre, L., Mellman, I. <strong>Endosomes are specialized platforms for bacterial sensing and NOD2 signalling.</strong> Nature 509: 240-244, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24695226/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24695226</a>] [<a href="https://doi.org/10.1038/nature13133" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24695226">Nakamura et al. (2014)</a> concluded that dendritic cell endosomes are specialized platforms for both the luminal and cytosolic sensing of pathogens. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24695226" 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 mouse and human cells, <a href="#24" class="mim-tip-reference" title="Keestra-Gounder, A. M., Byndloss, M. X., Seyffert, N., Young, B. M., Chavez-Arroyo, A., Tsai, A. Y., Cevallos, S. A., Winter, M. G., Pham, O. H., Tiffany, C. R., de Jong, M. F., Kerrinnes, T., Ravindran, R., Luciw, P. A., McSorley, S. J., Baumler, A. J., Tsolis, R. M. <strong>NOD1 and NOD2 signalling links ER stress with inflammation.</strong> Nature 532: 394-397, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27007849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27007849</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27007849[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/nature17631" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27007849">Keestra-Gounder et al. (2016)</a> identified NOD1 and NOD2 as mediators of inflammation induced by endoplasmic reticulum (ER) stress. Induction of ER stress triggered IL6 (<a href="/entry/147620">147620</a>) production in an NOD1/NOD2-dependent manner. Infection of mice with Brucella abortus, which induces ER stress in a TLR-independent manner, triggered inflammation and Il6 production in a Traf2 (<a href="/entry/601895">601895</a>)-, Nod1/Nod2-, and Rip2-dependent manner. B. abortus-induced inflammation and Il6 production could be reduced by treatment with an ER-stress inhibitor or an Ire1a (ERN1; <a href="/entry/604033">604033</a>) kinase inhibitor. <a href="#24" class="mim-tip-reference" title="Keestra-Gounder, A. M., Byndloss, M. X., Seyffert, N., Young, B. M., Chavez-Arroyo, A., Tsai, A. Y., Cevallos, S. A., Winter, M. G., Pham, O. H., Tiffany, C. R., de Jong, M. F., Kerrinnes, T., Ravindran, R., Luciw, P. A., McSorley, S. J., Baumler, A. J., Tsolis, R. M. <strong>NOD1 and NOD2 signalling links ER stress with inflammation.</strong> Nature 532: 394-397, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27007849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27007849</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27007849[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/nature17631" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27007849">Keestra-Gounder et al. (2016)</a> concluded that an NOD1/NOD2-dependent pathway mediates ER-stress-induced proinflammatory responses, providing a link between NOD1, NOD2, and inflammatory diseases involving ER stress, such as Crohn disease and type-2 diabetes (NIDDM; <a href="/entry/125853">125853</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27007849" 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 human commensal Bacteroides fragilis delivers immunomodulatory molecules to immune cells via secretion of outer membrane vesicles (OMVs). <a href="#5" class="mim-tip-reference" title="Chu, H., Khosravi, A., Kusumawardhani, I. P., Kwon, A. H. K., Vasconcelos, A. C., Cunha, L. D., Mayer, A. E., Shen, Y., Wu, W.-L., Kambal, A., Targan, S. R., Xavier, R. J., Ernst, P. B., Green, D. R., McGovern, D. P. B., Virgin, H. W., Mazmanian, S. K. <strong>Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease.</strong> Science 352: 1116-1120, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27230380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27230380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27230380[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aad9948" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27230380">Chu et al. (2016)</a> found that OMVs require the inflammatory bowel disease (IBD; see <a href="/entry/266600">266600</a>)-associated genes ATG16L1 and NOD2 to activate a noncanonical autophagy pathway during protection from colitis. ATG16L1-deficient dendritic cells do not induce regulatory T cells (T(regs)) to suppress mucosal inflammation. Immune cells from human subjects with a major risk variant in ATG16L1 are defective in T(reg) responses to OMVs. <a href="#5" class="mim-tip-reference" title="Chu, H., Khosravi, A., Kusumawardhani, I. P., Kwon, A. H. K., Vasconcelos, A. C., Cunha, L. D., Mayer, A. E., Shen, Y., Wu, W.-L., Kambal, A., Targan, S. R., Xavier, R. J., Ernst, P. B., Green, D. R., McGovern, D. P. B., Virgin, H. W., Mazmanian, S. K. <strong>Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease.</strong> Science 352: 1116-1120, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27230380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27230380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27230380[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aad9948" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27230380">Chu et al. (2016)</a> proposed that polymorphisms in susceptibility genes promote disease through defects in 'sensing' protective signals from the microbiome, defining a potentially critical gene-environment etiology for IBD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27230380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#39" class="mim-tip-reference" title="Ogura, Y., Bonen, D. K., Inohara, N., Nicolae, D. L., Chen, F. F., Ramos, R., Britton, H., Moran, T., Karaliuskas, R., Duerr, R. H., Achkar, J.-P., Brant, S. R., Bayless, T. M., Kirschner, B. S., Hanauer, S. B., Nunez, G., Cho, J. H. <strong>A frameshift mutation in Nod2 associated with susceptibility to Crohn's disease.</strong> Nature 411: 603-606, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11385577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11385577</a>] [<a href="https://doi.org/10.1038/35079114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11385577">Ogura et al. (2001)</a> and <a href="#19" class="mim-tip-reference" title="Hugot, J.-P., Chamaillard, M., Zouali, H., Lesage, S., Cezard, J.-P., Belaiche, J., Almer, S., Tysk, C., O'Morain, C. A., Gassull, M., Binder, V., Finkel, Y., and 8 others. <strong>Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.</strong> Nature 411: 599-603, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11385576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11385576</a>] [<a href="https://doi.org/10.1038/35079107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11385576">Hugot et al. (2001)</a> identified mutations in the NOD2 gene (see, e.g., <a href="#0001">605956.0001</a>-<a href="#0003">605956.0003</a>) that were associated with susceptibility to Crohn disease (IBD1; <a href="/entry/266600">266600</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11385576+11385577" 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="#35" class="mim-tip-reference" title="Murillo, L., Crusius, J. B. A., van Bodegraven, A. A., Alizadeh, B. Z., Pena, A. S. <strong>CARD15 gene and the classification of Crohn's disease.</strong> Immunogenetics 54: 59-61, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11976792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11976792</a>] [<a href="https://doi.org/10.1007/s00251-002-0440-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11976792">Murillo et al. (2002)</a> studied 130 Dutch patients with Crohn disease, with a median follow-up of 9.2 years, and 152 ethnically matched healthy controls. They confirmed reports that the CARD15 3020insC mutation (<a href="#0001">605956.0001</a>) increases susceptibility to Crohn disease, but could not confirm the relationship for the CARD15 low frequency G908R missense mutation (<a href="#0002">605956.0002</a>) reported by <a href="#39" class="mim-tip-reference" title="Ogura, Y., Bonen, D. K., Inohara, N., Nicolae, D. L., Chen, F. F., Ramos, R., Britton, H., Moran, T., Karaliuskas, R., Duerr, R. H., Achkar, J.-P., Brant, S. R., Bayless, T. M., Kirschner, B. S., Hanauer, S. B., Nunez, G., Cho, J. H. <strong>A frameshift mutation in Nod2 associated with susceptibility to Crohn's disease.</strong> Nature 411: 603-606, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11385577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11385577</a>] [<a href="https://doi.org/10.1038/35079114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11385577">Ogura et al. (2001)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11976792+11385577" 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="#29" class="mim-tip-reference" title="Lesage, S., Zouali, H., Cezard, J.-P., EPWG-IBD Group, Colombel, J.-F., EPIMAD Group, Belaiche, J., GETAID Group, Almer, S., Tysk, C., O'Morain, C., Gassull, M., Binder, V., Finkel, Y., Modigliani, R., Gower-Rousseau, C., Macry, J., Merlin, F., Chamaillard, M., Jannot, A.-S., Thomas, G., Hugot, J.-P. <strong>CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease.</strong> Am. J. Hum. Genet. 70: 845-857, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11875755/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11875755</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11875755[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/10.1086/339432" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11875755">Lesage et al. (2002)</a> reported mutation analysis of the CARD15 gene in 453 patients with Crohn disease, including 166 sporadic and 287 familial cases, 159 patients with ulcerative colitis (IBD1; <a href="/entry/266600">266600</a>), and 103 healthy control subjects. Although no mutations were found to be associated with ulcerative colitis, 50% of patients with Crohn disease carried at least 1 potential disease-causing mutation, including 17% who had a double mutation. There were 27 rare additional mutations. Each of 3 polymorphisms (R702W, <a href="#0003">605956.0003</a>; G908R, <a href="#0002">605956.0002</a>; and 1007fs, <a href="#0001">605956.0001</a>) were confirmed to be intermittently associated with susceptibility to Crohn disease. These 3 main variants represented 32%, 18%, and 31%, respectively, of the total Crohn disease mutations, whereas the total of the 27 rare mutations represented 19% of disease-causing mutations. Altogether, 93% of the mutations were located in the distal third of the gene. These observations confirmed the gene-dosage effect in Crohn disease. Patients with double-dose mutations were characterized by a younger age at onset, a more frequent stricturing phenotype, and a less frequent colonic involvement than were seen in those patients who had no mutation. The severity of the disease and extraintestinal manifestations were not different for any of the CARD15 genotypes. The proportion of familial and sporadic cases and the proportion of patients with smoking habits were similar in the groups of Crohn disease patients with or without mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11875755" 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>Among 483 Japanese patients with Crohn disease, <a href="#58" class="mim-tip-reference" title="Yamazaki, K., Takazoe, M., Tanaka, T., Ichimori, T., Nakamura, Y. <strong>Absence of mutation in the NOD2/CARD15 gene among 483 Japanese patients with Crohn's disease.</strong> J. Hum. Genet. 47: 469-472, 2002. Note: Erratum: J. Hum. Genet. 48: 397 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12202985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12202985</a>] [<a href="https://doi.org/10.1007/s100380200067" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12202985">Yamazaki et al. (2002)</a> tested for the 3 mutations found to be independent risk factors for Crohn disease in Caucasian patients (R702W, G908R, and 1007fs). None of these mutations was identified; only an R702Q substitution was found in a single patient. Direct sequencing of DNA from 96 of these patients in the regions containing the 3 reported major mutations detected no sequence alterations of consequence. <a href="#58" class="mim-tip-reference" title="Yamazaki, K., Takazoe, M., Tanaka, T., Ichimori, T., Nakamura, Y. <strong>Absence of mutation in the NOD2/CARD15 gene among 483 Japanese patients with Crohn's disease.</strong> J. Hum. Genet. 47: 469-472, 2002. Note: Erratum: J. Hum. Genet. 48: 397 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12202985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12202985</a>] [<a href="https://doi.org/10.1007/s100380200067" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12202985">Yamazaki et al. (2002)</a> therefore concluded that NOD2/CARD15 is not a major contributor to Crohn disease susceptibility in the Japanese. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12202985" 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>Crohn disease exhibits a 2- to 4-fold increased frequency in Jews as compared with other ethnic/racial groups. <a href="#48" class="mim-tip-reference" title="Sugimura, K., Taylor, K. D., Lin, Y., Hang, T., Wang, D., Tang, Y.-M., Fischel-Ghodsian, N., Targan, S. R., Rotter, J. I., Yang, H. <strong>A novel NOD2/CARD15 haplotype conferring risk for Crohn disease in Ashkenazi Jews.</strong> Am. J. Hum. Genet. 72: 509-518, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12577202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12577202</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12577202[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/10.1086/367848" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12577202">Sugimura et al. (2003)</a> sought additional NOD2 mutations in patients with CD, since the 3 coding variants that had been reported were found in only 30 to 40% of patients and could not account for all the linkage between CD and IBD1 locus (<a href="/entry/266600">266600</a>). They studied 64 Ashkenazi Jewish and 147 non-Jewish white families. After excluding the influence of the 3 independent disease-predisposing mutations (1007fs, G908R, and R702W), significant linkage of the IBD1 locus on chromosome 16 to Crohn disease was found in Jews, with 2 peaks at D16S403 (mean allele sharing (MAS) = 0.70) and D16S411 (MAS = 0.59). They observed an increased frequency of a haplotype carrying only the 268S variant in Jewish patients but not in non-Jews, suggesting the existence of a Jewish-specific additional disease-predisposing factor on this haplotype. Sequencing of this haplotype revealed a new variant: IVS8+158 (referred to as JW1; <a href="#0007">605956.0007</a>). The 268S-JW1 combination exhibited a further increased risk (odds ratio = 5.75, p = 0.0005) and the highest population-attributable risk (15.1%) for CD among reported disease-predisposing mutations in Jews. Thus, in Ashkenazi Jews, unrecognized population-specific predisposing factor(s) existed on the 268S-JW1 haplotype at the IBD1 locus. This factor may contribute to the higher risk for CD in Ashkenazi Jews as compared with non-Jews. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12577202" 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="#7" class="mim-tip-reference" title="Croucher, P. J. P., Mascheretti, S., Hampe, J., Huse, K., Frenzel, H., Stoll, M., Lu, T., Nikolaus, S., Yang, S.-K., Krawczak, M., Kim, W. H., Schreiber, S. <strong>Haplotype structure and association to Crohn's disease of CARD15 mutations in two ethnically divergent populations.</strong> Europ. J. Hum. Genet. 11: 6-16, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12529700/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12529700</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200897" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12529700">Croucher et al. (2003)</a> examined 23 SNPs in and around the CARD15 gene in large northern European and Korean samples of patients with CD and normal controls. In the European patients, they confirmed that the 3 disease-associated SNPs in CARD15 (R702W, G908R, and 1007fs) occur independently, but noted that they share a common background haplotype, suggesting a common origin and the possibility of an undiscovered, more strongly predisposing mutation. Korean CD patients have a phenotype identical to the European patients, but had not previously been screened for CARD15. The 3 disease-associated SNPs were absent and there was no evidence of association between CARD15 and CD. <a href="#7" class="mim-tip-reference" title="Croucher, P. J. P., Mascheretti, S., Hampe, J., Huse, K., Frenzel, H., Stoll, M., Lu, T., Nikolaus, S., Yang, S.-K., Krawczak, M., Kim, W. H., Schreiber, S. <strong>Haplotype structure and association to Crohn's disease of CARD15 mutations in two ethnically divergent populations.</strong> Europ. J. Hum. Genet. 11: 6-16, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12529700/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12529700</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200897" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12529700">Croucher et al. (2003)</a> concluded that the disease-associated mutations in Europeans, which are rare, arose after the Asian-European split. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12529700" 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="#52" class="mim-tip-reference" title="van Heel, D. A., Dechairo, B. M., Dawson, G., McGovern, D. P. B., Negoro, K., Carey, A. H., Cardon, L. R., Mackay, I., Jewell, D. P., Lench, N. J. <strong>The IBD6 Crohn's disease locus demonstrates complex interactions with CARD15 and IBD5 disease-associated variants.</strong> Hum. Molec. Genet. 12: 2569-2575, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12928481/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12928481</a>] [<a href="https://doi.org/10.1093/hmg/ddg281" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12928481">Van Heel et al. (2003)</a> performed a genomewide scan of 137 Crohn disease affected relative pairs from 112 families. The authors verified linkage of Crohn disease to regions on chromosome 3 (IBD9; <a href="/entry/608448">608448</a>; p = 0.0009) and X (p = 0.001) in their cohort. Linkage to chromosome 16 (IBD1; <a href="/entry/266600">266600</a>) was observed in Crohn disease pairs not possessing common CARD15 mutations (p = 0.0007), 25 cM q telomeric of CARD15. Evidence for linkage to chromosome 19 (IBD6; <a href="/entry/606674">606674</a>) was observed in Crohn disease pairs not possessing CARD15 mutations (p = 0.0001), and in pairs possessing 1 or 2 copies of the IBD5 (<a href="/entry/606348">606348</a>) risk haplotype (p = 0.0005), with significant evidence for genetic heterogeneity and epistasis, respectively. These analyses demonstrated the complex genetic basis to Crohn disease, and that the discovery of disease-causing variants may be used to aid identification of further susceptibility loci in complex diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12928481" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#47" class="mim-tip-reference" title="Stoll, M., Corneliussen, B., Costello, C. M., Waetzig, G. H., Mellgard, B., Koch, W. A., Rosenstiel, P., Albrecht, M., Croucher, P. J. P., Seegert, D., Nikolaus, S., Hampe, J., Lengauer, T., Pierrou, S., Foelsch, U. R., Mathew, C. G., Lagerstrom-Fermer, M., Schreiber, S. <strong>Genetic variation in DLG5 is associated with inflammatory bowel disease.</strong> Nature Genet. 36: 476-480, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15107852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15107852</a>] [<a href="https://doi.org/10.1038/ng1345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15107852">Stoll et al. (2004)</a> identified variants in the DLG5 gene (<a href="/entry/604090">604090</a>) associated with inflammatory bowel disease. One of the risk-associated DLG5 haplotypes was distinguished from the common haplotype by a nonsynonymous single-nucleotide polymorphism (SNP) 113G-A, resulting in the amino acid substitution arg30-to-gln (R30Q) in the DUF622 domain of DLG5 (<a href="/entry/604090#0001">604090.0001</a>). The mutation was predicted to impede scaffolding of DLG5. They stratified the study sample according to the presence of risk-associated variants of CARD15 (1007fs, also known as 3020insC, <a href="#0001">605956.0001</a>; G908R, <a href="#0002">605956.0002</a>; R702W, <a href="#0003">605956.0003</a>) to study potential gene-gene interaction. They found a significant difference in association of the 113A variant of DLG5 with Crohn disease in affected individuals carrying the risk-associated CARD15 alleles versus those carrying non-risk-associated CARD15 alleles. This suggested a complex pattern of gene-gene interaction between DLG5 and CARD15, reflecting the complex nature of polygenic diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15107852" 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 a study of 193 Jewish Israeli CD patients, <a href="#23" class="mim-tip-reference" title="Karban, A., Eliakim, R. <strong>Failure to replicate the association of the novel NOD2/CARD15 haplotype (S268P-JW1) to Crohn's disease in the Jewish Israeli population. (Letter)</strong> Gastroenterology 126: 624-625, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14765395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14765395</a>] [<a href="https://doi.org/10.1053/j.gastro.2003.12.026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14765395">Karban and Eliakim (2004)</a> failed to replicate the association of the NOD2 IVS+158 variant with Crohn disease, but noted that they found similarity with the results of <a href="#48" class="mim-tip-reference" title="Sugimura, K., Taylor, K. D., Lin, Y., Hang, T., Wang, D., Tang, Y.-M., Fischel-Ghodsian, N., Targan, S. R., Rotter, J. I., Yang, H. <strong>A novel NOD2/CARD15 haplotype conferring risk for Crohn disease in Ashkenazi Jews.</strong> Am. J. Hum. Genet. 72: 509-518, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12577202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12577202</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12577202[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/10.1086/367848" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12577202">Sugimura et al. (2003)</a> with regard to the overall risk of carrying 1 of the 3 predisposing CD risk variants (1007fs, G908R, and R702W). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12577202+14765395" 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="#30" class="mim-tip-reference" title="Li, J., Moran, T., Swanson, E., Julian, C., Harris, J., Bonen, D. K., Hedl, M., Nicolae, D. L., Abraham, C., Cho, J. H. <strong>Regulation of IL-8 and IL-1-beta expression in Crohn's disease associated NOD2/CARD15 mutations.</strong> Hum. Molec. Genet. 13: 1715-1725, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15198989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15198989</a>] [<a href="https://doi.org/10.1093/hmg/ddh182" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15198989">Li et al. (2004)</a> defined cytokine regulation in mononuclear cells, with muramyl dipeptide (MDP), the minimal NOD2/CARD15 activating component of peptidoglycan. MDP induced a broad array of transcripts, including interleukin-1-beta (IL1B; <a href="/entry/147720">147720</a>) and interleukin-8 (IL8; <a href="/entry/146930">146930</a>). Leu1007fsinsC homozygotes demonstrated decreased transcriptional response to MDP. Modest induction of IL8 protein was observed in G908R and R702W homozygotes, indicating varying MDP sensitivity of the CD-associated mutations. With MDP plus TNF-alpha (TNFA; <a href="/entry/191160">191160</a>), there was a synergistic induction of IL1B secretion. In leu1007fsinsC homozygotes, there was a profound defect in IL1B secretion despite marked induction of IL1B mRNA. <a href="#30" class="mim-tip-reference" title="Li, J., Moran, T., Swanson, E., Julian, C., Harris, J., Bonen, D. K., Hedl, M., Nicolae, D. L., Abraham, C., Cho, J. H. <strong>Regulation of IL-8 and IL-1-beta expression in Crohn's disease associated NOD2/CARD15 mutations.</strong> Hum. Molec. Genet. 13: 1715-1725, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15198989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15198989</a>] [<a href="https://doi.org/10.1093/hmg/ddh182" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15198989">Li et al. (2004)</a> concluded that there is posttranscriptional dependency on the CARD15 pathway for IL1B secretion with MDP and TNF-alpha treatment and suggested that a signaling defect of innate immunity to MDP may be an essential underlying defect in the pathogenesis of some CD patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15198989" 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="#53" class="mim-tip-reference" title="van Heel, D. A., Ghosh, S., Butler, M., Hunt, K. A., Lundberg, A. M. C., Ahmad, T., McGovern, D. P. B., Onnie, C., Negoro, K., Goldthorpe, S., Foxwell, B. M. J., Mathew, C. G., Forbes, A., Jewell, D. P., Playford, R. J. <strong>Muramyl dipeptide and toll-like receptor sensitivity in NOD2-associated Crohn's disease. (Letter)</strong> Lancet 365: 1794-1796, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15910952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15910952</a>] [<a href="https://doi.org/10.1016/S0140-6736(05)66582-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15910952">Van Heel et al. (2005)</a> analyzed the cytokine response of peripheral blood mononuclear cells to MDP. MDP induced strong IL8 secretion and substantially upregulated the secretion of TNF-alpha and IL1B induced by Toll-like receptor (see <a href="/entry/601194">601194</a>) ligands. At low nanomolar MDP concentrations, these effects were abolished by the most common Crohn disease NOD2/CARD15 double-mutant genotypes (702W/1007fs, 702W/702W, 1007fs/1007fs, and 908R/1007fs). <a href="#53" class="mim-tip-reference" title="van Heel, D. A., Ghosh, S., Butler, M., Hunt, K. A., Lundberg, A. M. C., Ahmad, T., McGovern, D. P. B., Onnie, C., Negoro, K., Goldthorpe, S., Foxwell, B. M. J., Mathew, C. G., Forbes, A., Jewell, D. P., Playford, R. J. <strong>Muramyl dipeptide and toll-like receptor sensitivity in NOD2-associated Crohn's disease. (Letter)</strong> Lancet 365: 1794-1796, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15910952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15910952</a>] [<a href="https://doi.org/10.1016/S0140-6736(05)66582-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15910952">Van Heel et al. (2005)</a> suggested that NOD2 activation provides a priming signal to condition a broad early immune response to pathogens, and that the absence of this priming signal in NOD2-associated CD causes failure of early immune pathogen clearance and explains the abnormal adaptive immune responses to microbial antigens in CD patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15910952" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#38" class="mim-tip-reference" title="Netea, M. G., Ferwerda, G., de Jong, D. J., Werts, C., Boneca, I. G., Jehanno, M., Van Der Meer, J. W. M., Mengin-Lecreulx, D., Sansonetti, P. J., Philpott, D. J., Dharancy, S., Girardin, S. E. <strong>The frameshift mutation in Nod2 results in unresponsiveness not only to Nod2- but also to Nod1-activating peptidoglycan agonists.</strong> J. Biol. Chem. 280: 35859-35867, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16115863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16115863</a>] [<a href="https://doi.org/10.1074/jbc.M504924200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16115863">Netea et al. (2005)</a> investigated the responses of mononuclear cells from Crohn disease patients to MDP and other muramyl peptides and found that patients homozygous for the NOD2fs mutation were totally unresponsive to a diaminopimelic acid-containing muramyl tripeptide, the specific agonist for NOD1, and to gram-negative bacterial peptidoglycan. In contrast, a Crohn disease patient with the R702W mutation had normal responses to peptidoglycan. RT-PCR analysis indicated that patients with Nod2fs expressed significantly higher levels of peptidoglycan recognition protein S (PGLYRP1; <a href="/entry/604963">604963</a>), which may have contributed to the downregulation of NOD1-dependent responses. <a href="#38" class="mim-tip-reference" title="Netea, M. G., Ferwerda, G., de Jong, D. J., Werts, C., Boneca, I. G., Jehanno, M., Van Der Meer, J. W. M., Mengin-Lecreulx, D., Sansonetti, P. J., Philpott, D. J., Dharancy, S., Girardin, S. E. <strong>The frameshift mutation in Nod2 results in unresponsiveness not only to Nod2- but also to Nod1-activating peptidoglycan agonists.</strong> J. Biol. Chem. 280: 35859-35867, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16115863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16115863</a>] [<a href="https://doi.org/10.1074/jbc.M504924200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16115863">Netea et al. (2005)</a> concluded that there is unexpected cross-talk between the NOD1 and NOD2 signaling pathways and proposed that NOD1 functional defects may participate in the development of Crohn disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16115863" 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 summarizing previous findings, <a href="#26" class="mim-tip-reference" title="King, K., Sheikh, M. F., Cuthbert, A. P., Fisher, S. A., Onnie, C. M., Mirza, M. M., Pattni, R. C., Sanderson, J., Forbes, A., Mansfield, J., Lewis, C. M., Roberts, R. G., Mathew, C. G. <strong>Mutation, selection, and evolution of the Crohn disease susceptibility gene CARD15.</strong> Hum. Mutat. 27: 44-54, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16278823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16278823</a>] [<a href="https://doi.org/10.1002/humu.20264" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16278823">King et al. (2006)</a> stated that 3 common mutations in the CARD15 gene are associated with susceptibility to CD, and genetic data suggested a gene dosage model with an increased risk of 2- to 4-fold in heterozygotes and 20- to 40-fold in homozygotes. However, the discovery of numerous rare variants of CARD15 indicated that some heterozygotes with the common mutation have a rare mutation on the other CARD15 allele, which would support a recessive model for CD. <a href="#26" class="mim-tip-reference" title="King, K., Sheikh, M. F., Cuthbert, A. P., Fisher, S. A., Onnie, C. M., Mirza, M. M., Pattni, R. C., Sanderson, J., Forbes, A., Mansfield, J., Lewis, C. M., Roberts, R. G., Mathew, C. G. <strong>Mutation, selection, and evolution of the Crohn disease susceptibility gene CARD15.</strong> Hum. Mutat. 27: 44-54, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16278823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16278823</a>] [<a href="https://doi.org/10.1002/humu.20264" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16278823">King et al. (2006)</a> screened CARD15 for mutations in 100 CD patients who were heterozygous for 1 of those 3 common mutations. They developed a strategy for evaluating potential disease susceptibility alleles that involved assessing the degree of evolutionary conservation of involved residues, predicted effects on protein structure and function, and genotyping in a large sample of cases and controls. The evolutionary analysis was aided by sequencing the entire coding region of CARD15 in 3 primates (chimp, gibbon, and tamarin) and aligning the human sequence with these and orthologs from other species. They found that 11 of the 100 CD patients screened had a second potential pathogenic mutation within the exonic and periexonic sequences examined. Assuming that there are no additional pathogenic mutations in noncoding regions, the study of <a href="#26" class="mim-tip-reference" title="King, K., Sheikh, M. F., Cuthbert, A. P., Fisher, S. A., Onnie, C. M., Mirza, M. M., Pattni, R. C., Sanderson, J., Forbes, A., Mansfield, J., Lewis, C. M., Roberts, R. G., Mathew, C. G. <strong>Mutation, selection, and evolution of the Crohn disease susceptibility gene CARD15.</strong> Hum. Mutat. 27: 44-54, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16278823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16278823</a>] [<a href="https://doi.org/10.1002/humu.20264" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16278823">King et al. (2006)</a> suggested that most carriers of the common disease susceptibility alleles are true heterozygotes, and supported evidence for a gene dosage model. Four novel nonsynonymous mutations were detected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16278823" 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="#33" class="mim-tip-reference" title="Medici, V., Mascheretti, S., Croucher, P. J. P., Stoll, M., Hampe, J., Grebe, J., Sturniolo, G. C., Solberg, C., Jahnsen, J., Moum, B., Schreiber, S., Vatn, M. H. <strong>Extreme heterogeneity in CARD15 and DLG5 Crohn disease-associated polymorphisms between German and Norwegian populations.</strong> Europ. J. Hum. Genet. 14: 459-468, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16493449/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16493449</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201576" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16493449">Medici et al. (2006)</a> studied 23 CARD15 SNPs in a Norwegian population of 476 unrelated IBD patients and 236 controls in comparison to a well-studied German population of IBD patients and controls. They found significantly lower frequencies of the predisposing CARD15 SNPs (1007fs, G908R, and R702W) and no significant associations with CD in the Norwegian samples. The population-attributable risk percentage of the 3 CARD15 variants in the Norwegian cohort was one of the lowest reported for a European population (1.88%). <a href="#33" class="mim-tip-reference" title="Medici, V., Mascheretti, S., Croucher, P. J. P., Stoll, M., Hampe, J., Grebe, J., Sturniolo, G. C., Solberg, C., Jahnsen, J., Moum, B., Schreiber, S., Vatn, M. H. <strong>Extreme heterogeneity in CARD15 and DLG5 Crohn disease-associated polymorphisms between German and Norwegian populations.</strong> Europ. J. Hum. Genet. 14: 459-468, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16493449/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16493449</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201576" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16493449">Medici et al. (2006)</a> stated that these results are consistent with a low frequency of the CARD15 variants in the northern European countries where the prevalence of IBD is greatest. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16493449" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="MacArthur, D. G., Balasubramanian, S., Frankish, A., Huang, N., Morris, J., Walter, K., Jostins, L., Habegger, L., Pickrell, J. K., Montgomery, S. B., Albers, C. A., Zhang, Z. D., and 40 others. <strong>A systematic survey of loss-of-function variants in human protein-coding genes.</strong> Science 335: 823-828, 2012. Note: Erratum: Science 336: 296 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22344438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22344438</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22344438[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1215040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22344438">MacArthur et al. (2012)</a> performed a systematic survey of loss-of-function variants in human protein-coding genes from the 1000 Genomes Study and imputed 417 loss-of-function single-nucleotide variants and indels into a total of 13,241 patients representing 7 complex diseases, such as Crohn disease and rheumatory arthritis, along with 2,938 shared controls, who had previously been subjected to genomewide SNP genotyping (45:<a href="#57" class="mim-tip-reference" title="Wellcome Trust Case Control Consortium. <strong>Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.</strong> Nature 447: 661-678, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17554300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17554300</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17554300[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/nature05911" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17554300">Wellcome Trust Case Control Consortium, 2007</a>). <a href="#31" class="mim-tip-reference" title="MacArthur, D. G., Balasubramanian, S., Frankish, A., Huang, N., Morris, J., Walter, K., Jostins, L., Habegger, L., Pickrell, J. K., Montgomery, S. B., Albers, C. A., Zhang, Z. D., and 40 others. <strong>A systematic survey of loss-of-function variants in human protein-coding genes.</strong> Science 335: 823-828, 2012. Note: Erratum: Science 336: 296 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22344438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22344438</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22344438[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1215040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22344438">MacArthur et al. (2012)</a> confirmed a previously known frameshift indel in the NOD2 gene (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2066847;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2066847</a>, <a href="#0012">605956.0012</a>) associated with Crohn disease with a genomewide-significant imputed P value of 1.78 x 10(-14) (2 orders of magnitude more significant than the best tag SNP). However, no other loss-of-function variants achieved genomewide significance, suggesting that common gene-disrupting variants play a minor role in complex disease predisposition. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17554300+22344438" 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="#44" class="mim-tip-reference" title="Rivas, M. A., Beaudoin, M., Gardet, A., Stevens, C., Sharma, Y., Zhang, C. K., Boucher, G., Ripke, S., Ellinghaus, D., Burtt, N., Fennell, T., Kirby, A., and 29 others. <strong>Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease.</strong> Nature Genet. 43: 1066-1073, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21983784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21983784</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21983784[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/ng.952" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21983784">Rivas et al. (2011)</a> used pooled next-generation sequencing to study 56 genes from regions associated with Crohn disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in 9 independent case-control series (16,054 Crohn disease cases, 12,153 ulcerative colitis cases, and 17,575 healthy controls), they identified 4 additional independent risk factors in NOD2: R311W, S431L, R703C, and N852S. N852S occurred only in Ashkenazi Jewish individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21983784" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Blau Syndrome</em></strong></p><p>
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Blau syndrome (<a href="/entry/186580">186580</a>) is a rare autosomal dominant disorder characterized by early-onset granulomatous arthritis, uveitis, and skin rash with camptodactyly. In affected members of 4 families with Blau syndrome, <a href="#34" class="mim-tip-reference" title="Miceli-Richard, C., Lesage, S., Rybojad, M., Prieur, A.-M., Manouvrier-Hanu, S., Hafner, R., Chamaillard, M., Zouali, H., Thomas, G., Hugot, J.-P. <strong>CARD15 mutations in Blau syndrome.</strong> Nature Genet. 29: 19-20, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11528384/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11528384</a>] [<a href="https://doi.org/10.1038/ng720" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11528384">Miceli-Richard et al. (2001)</a> identified 3 different heterozygous mutations in the CARD15 gene (R334Q, <a href="#0004">605956.0004</a>; L469F, <a href="#0005">605956.0005</a>; and R334W, <a href="#0006">605956.0006</a>). All mutations were located in the region encoding the nucleotide binding domain of CARD15; mutations identified patients with Crohn disease were located in the leucine-rich repeat domain of CARD15. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11528384" 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 a 27-year-old Japanese man with systemic granulomatous disease, in whom lack of a family history of the disease led to a diagnosis of 'early-onset sarcoidosis' rather than Blau syndrome, <a href="#20" class="mim-tip-reference" title="Kanazawa, N., Matsushima, S., Kambe, N., Tachibana, T., Nagai, S., Miyachi, Y. <strong>Presence of a sporadic case of systemic granulomatosis syndrome with a CARD15 mutation.</strong> J. Invest. Derm. 122: 851-852, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15086578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15086578</a>] [<a href="https://doi.org/10.1111/j.0022-202X.2004.22341.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15086578">Kanazawa et al. (2004)</a> identified 1 of the same CARD15 mutations (R334W; <a href="#0006">605956.0006</a>) as detected in Blau syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15086578" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Kanazawa, N., Okafuji, I., Kambe, N., Nishikomori, R., Nakata-Hizume, M., Nagai, S., Fuji, A., Yuasa, T., Manki, A., Sakurai, Y., Nakajima, M., Kobayashi, H., Fujiwara, I., Tsutsumi, H., Utani, A., Nishigori, C., Heike, T., Nakahata, T., Miyachi, Y. <strong>Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappa-B activation: common genetic etiology with Blau syndrome.</strong> Blood 105: 1195-1197, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15459013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15459013</a>] [<a href="https://doi.org/10.1182/blood-2004-07-2972" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15459013">Kanazawa et al. (2005)</a> retrospectively collected Japanese 'early-onset sarcoidosis' cases in search of CARD15 mutations. Among 10 of these patients, including the patient previously studied by <a href="#20" class="mim-tip-reference" title="Kanazawa, N., Matsushima, S., Kambe, N., Tachibana, T., Nagai, S., Miyachi, Y. <strong>Presence of a sporadic case of systemic granulomatosis syndrome with a CARD15 mutation.</strong> J. Invest. Derm. 122: 851-852, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15086578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15086578</a>] [<a href="https://doi.org/10.1111/j.0022-202X.2004.22341.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15086578">Kanazawa et al. (2004)</a>, missense mutations were found in 9: 4 were heterozygous for the R334W mutation (<a href="#0006">605956.0006</a>) that had been reported in patients diagnosed with Blau syndrome; 4 were heterozygous for different novel missense mutations (see, e.g., <a href="#0008">605956.0008</a>); and 1 patient had 2 missense mutations (D382E, <a href="#0009">605956.0009</a> and A612T, <a href="#0010">605956.0010</a>). (The pathogenicity of the A612T variant was later called into question.) All of these variants of CARD15 showed increased basal NFKB activity. <a href="#21" class="mim-tip-reference" title="Kanazawa, N., Okafuji, I., Kambe, N., Nishikomori, R., Nakata-Hizume, M., Nagai, S., Fuji, A., Yuasa, T., Manki, A., Sakurai, Y., Nakajima, M., Kobayashi, H., Fujiwara, I., Tsutsumi, H., Utani, A., Nishigori, C., Heike, T., Nakahata, T., Miyachi, Y. <strong>Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappa-B activation: common genetic etiology with Blau syndrome.</strong> Blood 105: 1195-1197, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15459013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15459013</a>] [<a href="https://doi.org/10.1182/blood-2004-07-2972" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15459013">Kanazawa et al. (2005)</a> concluded that most patients given a diagnosis of early-onset sarcoidosis or Blau syndrome share a common genetic etiology of CARD15 mutations that cause constitutive NFKB activation, and noted that this supported the long-standing hypothesis that sporadic cases of early-onset sarcoidosis and familial cases of Blau syndrome represent different types of the same juvenile systemic granulomatosis syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15086578+15459013" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Goyal, M., Cohen, M. L., Bangert, B. A., Robinson, S., Singer, N. G. <strong>Rasmussen syndrome and CNS granulomatous disease with NOD2/CARD15 mutations.</strong> Neurology 69: 640-643, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17698784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17698784</a>] [<a href="https://doi.org/10.1212/01.wnl.0000267429.89675.03" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17698784">Goyal et al. (2007)</a> reported an unusual case of a 12-year-old girl who presented with persistent focal seizures and MRI signal abnormalities. Brain biopsies showed marked dural granulomatous inflammation with focal extension into the brain parenchyma. Studies for systemic sarcoidosis were negative. Treatment with infliximab, a TNF-alpha inhibitor, resulted in clinical improvement. Family history revealed a paternal uncle and grandfather with Crohn disease, and molecular analysis identified 3 missense mutations in the NOD2 gene in the proband. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17698784" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Susceptibility to Yao Syndrome</em></strong></p><p>
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In 7 unrelated patients with multisystem autoinflammatory disease (YAOS; <a href="/entry/617321">617321</a>), <a href="#62" class="mim-tip-reference" title="Yao, Q., Zhou, L., Cusumano, P., Bose, N., Piliang, M., Jayakar, B., Su, L.-C., Shen, B. <strong>A new category of autoinflammatory disease associated with NOD2 gene mutations.</strong> Arthritis Res. Ther. 13: R148, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21914217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21914217</a>] [<a href="https://doi.org/10.1186/ar3462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21914217">Yao et al. (2011)</a> identified heterozygosity for a known intronic variant in the NOD2 gene, IVS8+158 (<a href="#0007">605956.0007</a>). Four of the patients also carried the R702W mutation (<a href="#0003">605956.0003</a>) in NOD2. <a href="#62" class="mim-tip-reference" title="Yao, Q., Zhou, L., Cusumano, P., Bose, N., Piliang, M., Jayakar, B., Su, L.-C., Shen, B. <strong>A new category of autoinflammatory disease associated with NOD2 gene mutations.</strong> Arthritis Res. Ther. 13: R148, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21914217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21914217</a>] [<a href="https://doi.org/10.1186/ar3462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21914217">Yao et al. (2011)</a> stated that the clinical relevance of these gene mutations remained to be determined, and that this disease might be genetically complex rather than mendelian. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21914217" 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 22 patients with autoinflammatory disease, including the 7 patients previously studied by <a href="#62" class="mim-tip-reference" title="Yao, Q., Zhou, L., Cusumano, P., Bose, N., Piliang, M., Jayakar, B., Su, L.-C., Shen, B. <strong>A new category of autoinflammatory disease associated with NOD2 gene mutations.</strong> Arthritis Res. Ther. 13: R148, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21914217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21914217</a>] [<a href="https://doi.org/10.1186/ar3462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21914217">Yao et al. (2011)</a>, <a href="#61" class="mim-tip-reference" title="Yao, Q., Su, L.-C., Tomecki, K. J., Zhou, L., Jayakar, B., Shen, B. <strong>Dermatitis as a characteristic phenotype of a new autoinflammatory disease associated with NOD2 mutations.</strong> J. Am. Acad. Derm. 68: 624-631, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23102769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23102769</a>] [<a href="https://doi.org/10.1016/j.jaad.2012.09.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23102769">Yao et al. (2013)</a> screened the NOD2 gene and found that all carried at least 1 variant: 21 had the IVS8+158 variant, and 8 had the R702W variant. <a href="#61" class="mim-tip-reference" title="Yao, Q., Su, L.-C., Tomecki, K. J., Zhou, L., Jayakar, B., Shen, B. <strong>Dermatitis as a characteristic phenotype of a new autoinflammatory disease associated with NOD2 mutations.</strong> J. Am. Acad. Derm. 68: 624-631, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23102769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23102769</a>] [<a href="https://doi.org/10.1016/j.jaad.2012.09.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23102769">Yao et al. (2013)</a> suggested that the IVS8+158 variant, particularly in conjunction with the R702W variant, may confer a considerably higher risk of NOD2-associated autoinflammatory disease. The authors also stated that this disorder differed markedly from Blau syndrome (<a href="/entry/186580">186580</a>), since these patients commonly exhibited spongiotic dermatitis rather than the granulomatous dermatitis of Blau syndrome, and none showed the chronic joint deformity (camptodactyly) and uveitis typical of Blau syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21914217+23102769" 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="#60" class="mim-tip-reference" title="Yao, Q., Shen, M., McDonald, C., Lacbawan, F., Moran, R., Shen, B. <strong>NOD2-associated autoinflammatory disease: a large cohort study.</strong> Rheumatology 54: 1904-1912, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26070941/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26070941</a>] [<a href="https://doi.org/10.1093/rheumatology/kev207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26070941">Yao et al. (2015)</a> genotyped 143 patients with symptoms suggestive of Yao syndrome for NOD2 variants and identified 54 patients who fulfilled criteria for Yao syndrome, including the presence of NOD2 variants. The IVS8+158 variant was detected in 46 of the 54 patients, including 30 who carried only IVS8+158 and 18 who also carried other known variants, including R702W, 1007fs (<a href="#0001">605956.0001</a>), and G908R (<a href="#0002">605956.0002</a>). In addition, 9 other rare NOD2 variants were detected in 13 of the patients. <a href="#60" class="mim-tip-reference" title="Yao, Q., Shen, M., McDonald, C., Lacbawan, F., Moran, R., Shen, B. <strong>NOD2-associated autoinflammatory disease: a large cohort study.</strong> Rheumatology 54: 1904-1912, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26070941/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26070941</a>] [<a href="https://doi.org/10.1093/rheumatology/kev207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26070941">Yao et al. (2015)</a> noted that it remained unclear whether these variants were causative or served as markers indirectly associated with the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26070941" 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="#59" class="mim-tip-reference" title="Yao, Q., Kontzias, A. <strong>Expansion of phenotypic and genotypic spectrum in Yao syndrome: a case series.</strong> J. Clin. Rheum. 28: e156-e160, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33394828/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33394828</a>] [<a href="https://doi.org/10.1097/RHU.0000000000001655" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33394828">Yao and Kontzias (2022)</a> identified mutations in the NOD2 gene in 11 patients with YAOS; 5 patients had a single mutation (3 with IVS8+158), 5 patients had biallelic mutations (all with IVS8+158 on 1 allele), and 1 patient had 3 mutations. The mutations were identified by next-generation sequencing of a panel of genes associated with periodic fever syndromes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33394828" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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<a href="#22" class="mim-tip-reference" title="Karason, A., Gudjonsson, J. E., Upmanyu, R., Antonsdottir, A. A., Hauksson, V. B., Runasdottir, E. H., Jonsson, H. H., Gudbjartsson, D. F., Frigge, M. L., Kong, A., Stefansson, K., Valdimarsson, H., Gulcher, J. R. <strong>A susceptibility gene for psoriatic arthritis maps to chromosome 16p: evidence for imprinting.</strong> Am. J. Hum. Genet. 72: 125-131, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12474146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12474146</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12474146[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/10.1086/345646" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12474146">Karason et al. (2003)</a> performed a genomewide linkage scan in psoriatic arthritis in a group of 178 patients from 39 Icelandic families and found a lod score of 2.17 on 16q (<a href="/entry/607507">607507</a>). Further analysis, conditional on paternal transmission to affected individuals, resulted in a lod score of 4.19. The peak of this lod score was within 20 Mb of the CARD15 gene. The region overlapping CARD15 had been implicated by a genomewide scan in psoriasis by <a href="#36" class="mim-tip-reference" title="Nair, R. P., Henseler, T., Jenisch, S., Stuart, P., Bichakjian, C. K., Lenk, W., Westphal, E., Guo, S.-W., Christophers, E., Voorhees, J. J., Elder, J. T. <strong>Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan.</strong> Hum. Molec. Genet. 6: 1349-1356, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9259283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9259283</a>] [<a href="https://doi.org/10.1093/hmg/6.8.1349" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9259283">Nair et al. (1997)</a>. The possibility of a common susceptibility gene shared by psoriasis/psoriatic arthritis and Crohn disease was further supported by epidemiologic studies that noted an increased incidence of psoriasis and psoriatic arthritis in subjects with Crohn disease (<a href="#28" class="mim-tip-reference" title="Lee, F. I., Bellary, S. V., Francis, C. <strong>Increased occurrence of psoriasis in patients with Crohn's disease and their relatives.</strong> Am. J. Gastroent. 85: 962-963, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2375323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2375323</a>]" pmid="2375323">Lee et al., 1990</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9259283+2375323+12474146" 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 Newfoundland, <a href="#43" class="mim-tip-reference" title="Rahman, P., Bartlett, S., Siannis, F., Pellett, F. J., Farewell, V. T., Peddle, L., Schentag, C. T., Alderdice, C. A., Hamilton, S., Khraishi, M., Tobin, Y., Hefferton, D., Gladman, D. D. <strong>CARD15: a pleiotropic autoimmune gene that confers susceptibility to psoriatic arthritis.</strong> Am. J. Hum. Genet. 73: 677-681, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12879366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12879366</a>] [<a href="https://doi.org/10.1086/378076" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12879366">Rahman et al. (2003)</a> screened 187 patients with psoriatic arthritis and 136 healthy controls for the 3 common, independent sequence variants of CARD15: R702W (<a href="#0003">605956.0003</a>), leu1007fsinsC (<a href="#0001">605956.0001</a>), and G908R (<a href="#0002">605956.0002</a>). In total, 53 of 187 (28.3%) probands with psoriatic arthritis had at least 1 variant of the CARD15 gene, compared with 16 of 136 (11.8%) controls; odds ratio = 2.97, p = 0.0005. Allele frequencies of R702W, leu1007fsinsC, and G908R were 10.43%, 3.21%, and 1.61%, respectively, in patients with psoriatic arthritis, compared with 3.31%, 2.57%, and 0.37%, respectively, in the control patients. CARD15 conferred susceptibility to psoriatic arthritis independent of HLA-Cw*0602 (see HLA-C, <a href="/entry/142840">142840</a>), which of the HLA types shows the strongest association with psoriasis (<a href="#13" class="mim-tip-reference" title="Gladman, D. D. <strong>Current concepts in psoriatic arthritis.</strong> Curr. Opin. Rheum. 14: 361-366, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12118168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12118168</a>] [<a href="https://doi.org/10.1097/00002281-200207000-00005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12118168">Gladman, 2002</a>). <a href="#43" class="mim-tip-reference" title="Rahman, P., Bartlett, S., Siannis, F., Pellett, F. J., Farewell, V. T., Peddle, L., Schentag, C. T., Alderdice, C. A., Hamilton, S., Khraishi, M., Tobin, Y., Hefferton, D., Gladman, D. D. <strong>CARD15: a pleiotropic autoimmune gene that confers susceptibility to psoriatic arthritis.</strong> Am. J. Hum. Genet. 73: 677-681, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12879366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12879366</a>] [<a href="https://doi.org/10.1086/378076" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12879366">Rahman et al. (2003)</a> stated that CARD15 was the first candidate gene identified in psoriatic arthritis that resides outside the major histocompatibility complex. They referred to CARD15 as a pleiotropic autoimmune gene, since it confers susceptibility to Crohn disease, Blau syndrome, and psoriatic arthritis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12879366+12118168" 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="#17" class="mim-tip-reference" title="Hampe, J., Grebe, J., Nikolaus, S., Solberg, C., Croucher, P. J. P., Mascheretti, S., Jahnsen, J., Moum, B., Klump, B., Krawczak, M., Mirza, M. M., Foelsch, U. R., Vatn, M., Schreiber, S. <strong>Association of NOD2 (CARD 15) genotype with clinical course of Crohn's disease: a cohort study.</strong> Lancet 359: 1661-1665, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12020527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12020527</a>] [<a href="https://doi.org/10.1016/S0140-6736(02)08590-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12020527">Hampe et al. (2002)</a> investigated the relationship between specific NOD2 genotypes and phenotypic characteristics of patients with Crohn disease. Hypotheses were generated retrospectively from a group of 446 German patients with this disorder. Positive findings (p less than 0.100) were verified in prospectively established cohorts of 106 German and 55 Norwegian patients with Crohn disease. All patients were genotyped for the main coding mutations in NOD2, denoted SNP8 (R702W), SNP12 (G908R), and SNP13 (1007fs). In the retrospective cohort, 6 clinical characteristics showed noteworthy haplotype association: fistulizing, disease of the ileum and left and right colon, stenosis, and resection. In the German prospective cohort, these haplotype associations could be replicated for ileal disease (p = 0.006) and right colonic disease (p less than 0.001). A similar trend was noted in the Norwegian patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12020527" 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="#55" class="mim-tip-reference" title="Vermeire, S., Wild, G., Kocher, K., Cousineau, J., Dufresne, L., Bitton, A., Langelier, D., Pare, P., Lapointe, G., Cohen, A., Daly, M. J., Rioux, J. D. <strong>CARD15 genetic variation in a Quebec population: prevalence, genotype-phenotype relationship, and haplotype structure.</strong> Am. J. Hum. Genet. 71: 74-83, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12019468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12019468</a>] [<a href="https://doi.org/10.1086/341124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12019468">Vermeire et al. (2002)</a> collected a cohort of 231 patients with Crohn disease and 71 healthy control individuals from the Canadian province of Quebec to determine the prevalence of 3 sequence variants: leu1007fsinsC (<a href="#0001">605956.0001</a>), gly908 to arg (G908R; <a href="#0002">605956.0002</a>), and arg702 to trp (R702W; <a href="#0003">605956.0003</a>). In this cohort, 45.0% of patients with Crohn disease carried at least 1 variant in the CARD15 gene, compared with 9.0% of control individuals. Allele frequencies of R702W, G908R, and leu1007fsinsC were 12.9%, 5.2%, and 10.3% in patients with Crohn disease, compared with 4.2%, 0.7%, and 0.7% in control individuals, respectively. Analysis of the relationship between genotype and phenotype convincingly demonstrated that CARD15 variants are significantly associated with ileal disease involvement, as opposed to strictly colonic disease (P less than 0.001). Moreover, <a href="#55" class="mim-tip-reference" title="Vermeire, S., Wild, G., Kocher, K., Cousineau, J., Dufresne, L., Bitton, A., Langelier, D., Pare, P., Lapointe, G., Cohen, A., Daly, M. J., Rioux, J. D. <strong>CARD15 genetic variation in a Quebec population: prevalence, genotype-phenotype relationship, and haplotype structure.</strong> Am. J. Hum. Genet. 71: 74-83, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12019468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12019468</a>] [<a href="https://doi.org/10.1086/341124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12019468">Vermeire et al. (2002)</a> determined the haplotype structure surrounding this disease gene by genotyping 45 SNPs in the 177-kb region that contains the CARD15 gene. The structure helped clarify the history of these causal mutations. Their analysis showed that CARD15 involvement with Crohn disease is detectable by use of publicly available SNPs alone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12019468" 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="#54" class="mim-tip-reference" title="van Heel, D. A., McGovern, D. P. B., Cardon, L. R., Dechairo, B. M., Lench, N. J., Carey, A. H., Jewell, D. P. <strong>Fine mapping of the IBD1 locus did not identify Crohn disease-associated NOD2 variants: implications for complex disease genetics.</strong> Am. J. Med. Genet. 111: 253-259, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12210321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12210321</a>] [<a href="https://doi.org/10.1002/ajmg.10588" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12210321">Van Heel et al. (2002)</a> discussed difficulties facing microsatellite linkage and linkage disequilibrium mapping methods for identifying disease genes in complex traits. They used 27 microsatellite markers encompassing the IBD1 susceptibility locus in 131 sib pairs affected with Crohn disease and in a simplex family cohort. No evidence of linkage was observed, and microsatellite markers close to NOD2 did not show association. However, significant association was confirmed in 294 Crohn disease trios (2 parents and affected offspring) for the NOD2 variants R702W and leu1007fsinsC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12210321" 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 assays based on NFKB activation, <a href="#4" class="mim-tip-reference" title="Chamaillard, M., Philpott, D., Girardin, S. E., Zouali, H., Lesage, S., Chareyre, F., Bui, T. H., Giovannini, M., Zaehringer, U., Penard-Lacronique, V., Sansonetti, P. J., Hugot, J.-P., Thomas, G. <strong>Gene-environment interaction modulated by allelic heterogeneity in inflammatory diseases.</strong> Proc. Nat. Acad. Sci. 100: 3455-3460, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12626759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12626759</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12626759[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0530276100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12626759">Chamaillard et al. (2003)</a> showed that cytosolic CARD15 efficiently detects bacterial peptidoglycan (PGN), reminiscent of the PGN recognition protein surveillance mechanism in Drosophila. The 3 variants that are associated with Crohn disease and 13 additional variants carried by Crohn disease patients demonstrated impaired PGN-dependent response revealing null, hypomorphic, or dominant-negative properties. Quantitative parametrization of this response, computed from the patients' CARD15 genotypes, was predictive of several variable manifestations of Crohn disease. In contrast, CARD15 alleles associated with Blau syndrome (<a href="/entry/186580">186580</a>) promoted PGN-independent NFKB activation, an observation that accounts for the minimal microbial input in the etiology of this dominant, monogenic inflammatory disorder affecting solely aseptic sites. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12626759" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Fidder, H. H., Olschwang, S., Avidan, B., Zouali, H., Lang, A., Bardan, E., Picard, O., Bar-Meir, S., Colombel, J. F., Chowers, Y. <strong>Association between mutations in the CARD15 (NOD2) gene and Crohn's disease in Israeli Jewish patients.</strong> Am. J. Med. Genet. 121A: 240-244, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12923865/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12923865</a>] [<a href="https://doi.org/10.1002/ajmg.a.20209" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12923865">Fidder et al. (2003)</a> studied the frequency of 2 missense and 1 frameshift variant of CARD15 in Israeli Jewish Crohn disease and ulcerative colitis patients. The 2 missense mutations were R675W (<a href="#0003">605956.0003</a>) and G881R (<a href="#0002">605956.0002</a>); the frameshift mutation was 980FS981X (<a href="#0001">605956.0001</a>). Mutations in CARD15 were observed with significantly greater frequency in Crohn disease patients (46/170, 27%) than in ulcerative colitis patients (7/68, 10%) (p = 0.005). Homozygosity and compound heterozygosity was found only in 7 (4%) patients with Crohn disease as compared to none of the ulcerative colitis patients. Similar rates were observed in Ashkenazi and non-Ashkenazi Jewish patients. Age of onset of disease was lower in Ashkenazi mutation carriers as compared to noncarriers of Ashkenazi origin (18.7 vs 25.8 years, respectively). No other phenotypic characteristics could distinguish mutation carriers from noncarriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12923865" 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>To determine whether CARD15 mutations account for the higher prevalence of Crohn disease in Ashkenazi Jews, <a href="#49" class="mim-tip-reference" title="Tukel, T., Shalata, A., Present, D., Rachmilewitz, D., Mayer, L., Grant, D., Risch, N., Desnick, R. J. <strong>Crohn disease: frequency and nature of CARD15 mutations in Ashkenazi and Sephardi/Oriental Jewish families.</strong> Am. J. Hum. Genet. 74: 623-636, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15024686/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15024686</a>] [<a href="https://doi.org/10.1086/382226" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15024686">Tukel et al. (2004)</a> assessed the haplotypes and allele frequencies of the common mutations and variants in 219 members of 50 Ashkenazi Jewish and 53 members of 10 Sephardi/Oriental Jewish multiplex families with CD, in 36 Ashkenazi Jewish patients with sporadic CD, and in 246 Ashkenazi and 82 Sephardi/Oriental Jewish controls. A higher frequency of CARD15 mutations was found in Ashkenazi Jewish patients from multiplex families with CD from central (44%) versus eastern (24%) Europe, especially for the G908R and 1007fs mutations, and in Sephardi/Oriental Jewish patients (34.5%) compared with Ashkenazi (10.1%) or Sephardi/Oriental (5.4%) Jewish controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15024686" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Giachino, D., van Duist, M. M., Regazzoni, S., Gregori, D., Bardessono, M., Salacone, P., Scaglione, N., Sostegni, R., Sapone, N., Bresso, F., Sambataro, A., Gaia, E., Pera, A., Astegiano, M., De Marchi, M. <strong>Analysis of the CARD15 variants R702W, G908R and L1007fs in Italian IBD patients.</strong> Europ. J. Hum. Genet. 12: 206-212, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14747834/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14747834</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14747834">Giachino et al. (2004)</a> analyzed the 3 recurrent CARD15 variants (R702W, G908R, and 1007fs) in 184 CD and 92 UC Italian patients and in 177 healthy controls. They found significant associations for G908R and L1007fs with CD only. Analysis of mutation-phenotype correlations revealed an increased chance of mutation positivity in patients with strictures (OR, 2.76; 95% CI, 1.2-6.3) and fistulas (OR, 2.59; 95% CI 1.0-6.6), and a weaker association with ileal location of disease (OR, 3.03; 95% CI, 0.9-9.8). <a href="#12" class="mim-tip-reference" title="Giachino, D., van Duist, M. M., Regazzoni, S., Gregori, D., Bardessono, M., Salacone, P., Scaglione, N., Sostegni, R., Sapone, N., Bresso, F., Sambataro, A., Gaia, E., Pera, A., Astegiano, M., De Marchi, M. <strong>Analysis of the CARD15 variants R702W, G908R and L1007fs in Italian IBD patients.</strong> Europ. J. Hum. Genet. 12: 206-212, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14747834/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14747834</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14747834">Giachino et al. (2004)</a> concluded that the CARD15 genotype can serve as an explanatory variable for predicting the pattern of IBD presentation and progression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14747834" 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 <a href="#57" class="mim-tip-reference" title="Wellcome Trust Case Control Consortium. <strong>Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.</strong> Nature 447: 661-678, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17554300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17554300</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17554300[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/nature05911" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17554300">Wellcome Trust Case Control Consortium (2007)</a> described a joint genomewide association study using the Affymetrix GeneChip 500K Mapping Array Set, undertaken in the British population, which examined approximately 2,000 individuals for each of 7 major diseases and a shared set of approximately 3,000 controls. This analysis identified 9 associations with Crohn disease including CARD15, which was represented by <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs17221417;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs17221417</a> (p = 9.4 x 10(-12)). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17554300" 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>Analysis of the evolution of CARD15 revealed strong conservation of the encoded protein, with identity to the human sequence ranging from 99.1% in the chimp to 44.5% in fugu (<a href="#26" class="mim-tip-reference" title="King, K., Sheikh, M. F., Cuthbert, A. P., Fisher, S. A., Onnie, C. M., Mirza, M. M., Pattni, R. C., Sanderson, J., Forbes, A., Mansfield, J., Lewis, C. M., Roberts, R. G., Mathew, C. G. <strong>Mutation, selection, and evolution of the Crohn disease susceptibility gene CARD15.</strong> Hum. Mutat. 27: 44-54, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16278823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16278823</a>] [<a href="https://doi.org/10.1002/humu.20264" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16278823">King et al., 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16278823" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The mouse Nod2 locus is situated on chromosome 8 and comprises 12 exons, 11 of which encode the Nod2 protein. <a href="#41" class="mim-tip-reference" title="Ogura, Y., Saab, L., Chen, F. F., Benito, A., Inohara, N., Nunez, G. <strong>Genetic variation and activity of mouse Nod2, a susceptibility gene for Crohn's disease.</strong> Genomics 81: 369-377, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12676561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12676561</a>] [<a href="https://doi.org/10.1016/s0888-7543(03)00027-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12676561">Ogura et al. (2003)</a> performed sequence analysis of the mouse Nod2 gene from 45 different strains and identified extensive polymorphisms involving all exons of the gene. Studies of the polymorphisms demonstrated a conserved role for Nod2 in the response to bacterial components and suggested that selective evolutionary pressure exerted by pathogens may have contributed to the high level of variability of Nod2 sequences in both humans and mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12676561" 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="#42" class="mim-tip-reference" title="Pauleau, A.-L., Murray, P. J. <strong>Role of Nod2 in the response of macrophages to Toll-like receptor agonists.</strong> Molec. Cell. Biol. 23: 7531-7539, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14560001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14560001</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14560001[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.23.21.7531-7539.2003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14560001">Pauleau and Murray (2003)</a> generated mice lacking Nod2. Nod2 -/- mice were indistinguishable from wildtype mice and manifested no symptoms or pathology consistent with human Crohn disease. Macrophages of Nod2 -/- mice had nearly normal responses to TLR stimulation and to Ifng (<a href="/entry/147570">147570</a>) and Il10 (<a href="/entry/124092">124092</a>), which activate and deactivate macrophages, respectively. However, Nod2 -/- weanling mice better survived a lethal lipopolysaccharide (LPS) challenge than did wildtype weanling mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14560001" 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="#27" class="mim-tip-reference" title="Kobayashi, K. S., Chamaillard, M., Ogura, Y., Henegariu, O., Inohara, N., Nunez, G., Flavell, R. A. <strong>Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract.</strong> Science 307: 731-734, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15692051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15692051</a>] [<a href="https://doi.org/10.1126/science.1104911" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15692051">Kobayashi et al. (2005)</a> generated mice deficient in Nod2 by targeted disruption. Nod2-null mice were outwardly healthy and displayed normal lymphoid and myeloid cellular composition in the thymus and spleen. The mice also displayed no overt symptoms of intestinal inflammation when observed for up to 6 months. <a href="#27" class="mim-tip-reference" title="Kobayashi, K. S., Chamaillard, M., Ogura, Y., Henegariu, O., Inohara, N., Nunez, G., Flavell, R. A. <strong>Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract.</strong> Science 307: 731-734, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15692051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15692051</a>] [<a href="https://doi.org/10.1126/science.1104911" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15692051">Kobayashi et al. (2005)</a> showed that protective immunity mediated by Nod2 recognition of bacterial muramyl dipeptide is abolished in Nod2-deficient mice. The mice were susceptible to bacterial infection through oral delivery but not through intravenous or peritoneal delivery. Nod2 is required for the expression of a subgroup of intestinal antimicrobial peptides known as cryptdins. <a href="#27" class="mim-tip-reference" title="Kobayashi, K. S., Chamaillard, M., Ogura, Y., Henegariu, O., Inohara, N., Nunez, G., Flavell, R. A. <strong>Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract.</strong> Science 307: 731-734, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15692051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15692051</a>] [<a href="https://doi.org/10.1126/science.1104911" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15692051">Kobayashi et al. (2005)</a> concluded that the NOD2 protein is a critical mediator of bacterial immunity within the intestine, providing a possible mechanism for NOD2 mutations in Crohn disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15692051" 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="#56" class="mim-tip-reference" title="Watanabe, T., Kitani, A., Murray, P. J., Strober, W. <strong>NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses.</strong> Nature Immun. 5: 800-808, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15220916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15220916</a>] [<a href="https://doi.org/10.1038/ni1092" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15220916">Watanabe et al. (2004)</a> studied Nod2 -/- mice and determined that intact Nod2 signaling inhibits Tlr2 (<a href="/entry/603028">603028</a>)-driven activation of Nfkb (see <a href="/entry/164011">164011</a>), particularly its Rel subunit (<a href="/entry/164910">164910</a>). Nod2 deficiency or the presence of a Crohn disease-like Nod2 mutation increased Tlr2-mediated activation of Nfkb-Rel in association with enhanced Th1 responses. <a href="#56" class="mim-tip-reference" title="Watanabe, T., Kitani, A., Murray, P. J., Strober, W. <strong>NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses.</strong> Nature Immun. 5: 800-808, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15220916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15220916</a>] [<a href="https://doi.org/10.1038/ni1092" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15220916">Watanabe et al. (2004)</a> concluded that NOD2 signaling normally inhibits TLR2-driven Th1 responses by regulating NFKB signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15220916" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="Maeda, S., Hsu, L.-C., Liu, H., Bankston, L. A., Iimura, M., Kagnoff, M. F., Eckmann, L., Karin, M. <strong>Nod2 mutation in Crohn's disease potentiates NF-kappa-B activity and IL-1-beta processing.</strong> Science 307: 734-738, 2005. Note: Erratum: Science 308: 633 only, 2005. Note: Erratum: Science 333: 288 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15692052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15692052</a>] [<a href="https://doi.org/10.1126/science.1103685" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15692052">Maeda et al. (2005)</a> generated mice whose Nod2 locus harbors the homolog of the most common Crohn disease susceptibility allele, 3020insC (<a href="#0001">605956.0001</a>), which encodes a truncated protein lacking the last 33 amino acids. Homozygous Nod2 mutant mice were obtained at the expected mendelian ratio, were healthy, and showed no abnormalities of the gastrointestinal tract or other organs. The mutation had no effect on Nod2 mRNA or protein amounts in bone marrow-derived macrophages. Mutant mice exhibited elevated NFKB activation in response to bacteria-derived muramyl dipeptide and more efficient processing and secretion of the cytokine interleukin-1-beta (IL1B; <a href="/entry/147720">147720</a>). These effects were linked to increased susceptibility to bacteria-induced intestinal inflammation and identified NOD2 as a positive regulator of NFKB activation and IL1B secretion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15692052" 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 histopathologic analysis, <a href="#9" class="mim-tip-reference" title="Divangahi, M., Mostowy, S., Coulombe, F., Kozak, R., Guillot, L., Veyrier, F., Kobayashi, K. S., Flavell, R. A., Gros, P., Behr, M. A. <strong>NOD2-deficient mice have impaired resistance to Mycobacterium tuberculosis infection through defective innate and adaptive immunity.</strong> J. Immun. 181: 7157-7165, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18981137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18981137</a>] [<a href="https://doi.org/10.4049/jimmunol.181.10.7157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18981137">Divangahi et al. (2008)</a> showed that Nod2-deficient mice had reduced inflammatory responses but similar bacterial counts compared with wildtype mice in the first 2 months after infection with Mycobacterium tuberculosis. Nod2-deficient mice infected with the M. bovis BCG vaccine had decreased production of Tnf, Ifng, and Il12p40 (IL12B; <a href="/entry/161561">161561</a>) and reduced recruitment of Cd4 (<a href="/entry/186940">186940</a>)-positive and Cd8 (see <a href="/entry/186910">186910</a>)-positive T cells. After 6 months, the bacterial burden was increased in the Nod2-deficient mice and their survival was significantly reduced. <a href="#9" class="mim-tip-reference" title="Divangahi, M., Mostowy, S., Coulombe, F., Kozak, R., Guillot, L., Veyrier, F., Kobayashi, K. S., Flavell, R. A., Gros, P., Behr, M. A. <strong>NOD2-deficient mice have impaired resistance to Mycobacterium tuberculosis infection through defective innate and adaptive immunity.</strong> J. Immun. 181: 7157-7165, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18981137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18981137</a>] [<a href="https://doi.org/10.4049/jimmunol.181.10.7157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18981137">Divangahi et al. (2008)</a> concluded that NOD2 mediates resistance to mycobacterial infection via both innate and adaptive immunity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18981137" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Hruz, P., Zinkernagel, A. S., Jenikova, G., Botwin, G. J., Hugot, J.-P., Karin, M., Nizet, V., Eckmann, L. <strong>NOD2 contributes to cutaneous defense against Staphylococcus aureus through alpha-toxin-dependent innate immune activation.</strong> Proc. Nat. Acad. Sci. 106: 12873-12878, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19541630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19541630</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19541630[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0904958106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19541630">Hruz et al. (2009)</a> found that Nod2-deficient mice exhibited a delayed but ultimately exacerbated response to subcutaneous Staphylococcus aureus infection. Nod2 action was dependent on Il1b-amplified production of Il6 (<a href="/entry/147620">147620</a>), which promoted rapid bacterial killing by neutrophils. <a href="#18" class="mim-tip-reference" title="Hruz, P., Zinkernagel, A. S., Jenikova, G., Botwin, G. J., Hugot, J.-P., Karin, M., Nizet, V., Eckmann, L. <strong>NOD2 contributes to cutaneous defense against Staphylococcus aureus through alpha-toxin-dependent innate immune activation.</strong> Proc. Nat. Acad. Sci. 106: 12873-12878, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19541630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19541630</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19541630[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0904958106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19541630">Hruz et al. (2009)</a> concluded that NOD2 is not only involved in recognition of organisms in cytoplasm, but that it also contributes to recognition of pathogenic bacteria in the extracellular compartment that elaborate pore-forming toxins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19541630" 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>T helper-17 (Th17) cells are a subset of CD4-positive helper T cells characterized by secretion of IL17 (<a href="/entry/603149">603149</a>) and IL22 (<a href="/entry/605330">605330</a>). <a href="#11" class="mim-tip-reference" title="Geddes, K., Rubino, S. J., Magalhaes, J. G., Streutker, C., Le Bourhis, L., Cho, J. H., Robertson, S. J., Kim, C. J., Kaul, R., Philpott, D. J., Girardin, S. E. <strong>Identification of an innate T helper type 17 response to intestinal bacterial pathogens.</strong> Nature Med. 17: 837-844, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21666695/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21666695</a>] [<a href="https://doi.org/10.1038/nm.2391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21666695">Geddes et al. (2011)</a> infected mice with Citrobacter rodentium or Salmonella typhimurium species and observed triggering of early Il17 production that was crucial for host defense mediated by Cd4-positive helper T cells. Th17 responses occurred principally in the cecum and were mediated by innate Th17 cells that were regulated by Nod1 and Nod2. Mice lacking both Nod1 and Nod2 were unable to induce early Th17 responses due to insufficient Il6 production. <a href="#11" class="mim-tip-reference" title="Geddes, K., Rubino, S. J., Magalhaes, J. G., Streutker, C., Le Bourhis, L., Cho, J. H., Robertson, S. J., Kim, C. J., Kaul, R., Philpott, D. J., Girardin, S. E. <strong>Identification of an innate T helper type 17 response to intestinal bacterial pathogens.</strong> Nature Med. 17: 837-844, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21666695/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21666695</a>] [<a href="https://doi.org/10.1038/nm.2391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21666695">Geddes et al. (2011)</a> concluded that the NOD-innate Th17 axis, which is dependent on IL6 expression and requires intestinal microbiota for induction, is a key element of mucosal immunity against bacterial pathogens. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21666695" 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>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000334899 OR RCV000389442 OR RCV000416485 OR RCV001529584 OR RCV001701717 OR RCV001781184 OR RCV002260960 OR RCV002468553 OR RCV002512781 OR RCV003224089" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000334899, RCV000389442, RCV000416485, RCV001529584, RCV001701717, RCV001781184, RCV002260960, RCV002468553, RCV002512781, RCV003224089" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000334899...</a>
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<p><strong><em>Inflammatory Bowel Disease 1 (Crohn Disease), Susceptibility to</em></strong></p><p>
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<a href="#39" class="mim-tip-reference" title="Ogura, Y., Bonen, D. K., Inohara, N., Nicolae, D. L., Chen, F. F., Ramos, R., Britton, H., Moran, T., Karaliuskas, R., Duerr, R. H., Achkar, J.-P., Brant, S. R., Bayless, T. M., Kirschner, B. S., Hanauer, S. B., Nunez, G., Cho, J. H. <strong>A frameshift mutation in Nod2 associated with susceptibility to Crohn's disease.</strong> Nature 411: 603-606, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11385577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11385577</a>] [<a href="https://doi.org/10.1038/35079114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11385577">Ogura et al. (2001)</a> sequenced all coding exons and flanking introns of the NOD2 gene in 12 affected individuals from pure Crohn disease (IBD1; <a href="/entry/266600">266600</a>) families with increased linkage scores at D16S3396, which is tightly linked to NOD2, as well as in 4 case controls. In 3 Crohn disease patients, they identified a 1-bp insertion (C) at nucleotide 3020 (3020insC) in exon 11 of the NOD2 gene, resulting in a frameshift at the second nucleotide of codon 1007 (1007fs) and a leu1007-to-pro substitution in the tenth LRR, followed by a premature stop codon. The predicted truncated NOD2 protein contained 1,007 amino acids instead of the 1,040 amino acids of the wildtype protein. <a href="#39" class="mim-tip-reference" title="Ogura, Y., Bonen, D. K., Inohara, N., Nicolae, D. L., Chen, F. F., Ramos, R., Britton, H., Moran, T., Karaliuskas, R., Duerr, R. H., Achkar, J.-P., Brant, S. R., Bayless, T. M., Kirschner, B. S., Hanauer, S. B., Nunez, G., Cho, J. H. <strong>A frameshift mutation in Nod2 associated with susceptibility to Crohn's disease.</strong> Nature 411: 603-606, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11385577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11385577</a>] [<a href="https://doi.org/10.1038/35079114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11385577">Ogura et al. (2001)</a> observed preferential transmission from heterozygous parents to affected children of the 3020insC mutation (P of 0.0046). There was no preferential transmission of this mutation in families with ulcerative colitis. The frequency of the 3020insC mutation was 8.4% among Jewish Caucasians and 8.1% among non-Jewish Caucasians. The frequency among control Caucasians was 4.0%. The allele frequency of this mutation from 182 unrelated ulcerative colitis patients was 3.0%. The genotype frequencies of the 3020insC mutation in unrelated Crohn disease individuals was 11 homozygotes, 46 heterozygotes, and 359 wildtype homozygotes. The genotype-relative risk for heterozygous and homozygous 3020insC was 1.5 and 17.6, respectively, as compared with wildtype controls. Lipopolysaccharide (LPS) from various bacteria induced nuclear factor kappa-B (NFKB; see <a href="/entry/164011">164011</a>) activation in cells expressing wildtype NOD2, but not in cells transfected with control plasmid. Cells transfected with NOD2 carrying the 3020insC mutation had greatly diminished response to LPS, with the most significant reduction in response to Salmonella, Shigella, Klebsiella, Campylobacter, and Neisseria gonorrhoeae. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11385577" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Hugot, J.-P., Chamaillard, M., Zouali, H., Lesage, S., Cezard, J.-P., Belaiche, J., Almer, S., Tysk, C., O'Morain, C. A., Gassull, M., Binder, V., Finkel, Y., and 8 others. <strong>Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.</strong> Nature 411: 599-603, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11385576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11385576</a>] [<a href="https://doi.org/10.1038/35079107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11385576">Hugot et al. (2001)</a> independently identified this mutation in association with Crohn disease; however, because they used the 1,013-amino acid NOD2B sequence, they reported the mutation as a frameshift at codon 980. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11385576" 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="#16" class="mim-tip-reference" title="Hampe, J., Cuthbert, A., Croucher, P. J. P., Mirza, M. M., Mascheretti, S., Fisher, S., Frenzel, H., King, K., Hasselmeyer, A., MacPherson, A. J. S., Bridger, S., van Deventer, S., Forbes, A., Nikolaus, S., Lennard-Jones, J. E., Foelsch, U. R., Krawczak, M., Lewis, C., Schreiber, S., Mathew, C. G. <strong>Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations.</strong> Lancet 357: 1925-1928, 2001. Note: Erratum: Lancet 360: 806 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11425413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11425413</a>] [<a href="https://doi.org/10.1016/S0140-6736(00)05063-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11425413">Hampe et al. (2001)</a> studied the association between this mutation and inflammatory bowel disease in 512 affected individuals from 309 German or British families, 369 German trios (patients with sporadic inflammatory bowel disease and their unaffected parents), and 272 normal controls. Family-based association analyses were consistently positive in 95 British and 99 German affected sib pairs with Crohn disease; the association was confirmed in 304 German trios with Crohn disease. No association was seen in the 115 sib pairs and 65 trios with ulcerative colitis. The genotype-specific disease risks conferred by heterozygous and homozygous mutant genotypes were 2.6 and 42.1, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11425413" 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 genetically impaired intestinal barrier function has long been suspected to be a predisposing factor for Crohn disease. To test the association of CARD15 with intestinal permeability, <a href="#3" class="mim-tip-reference" title="Buhner, S., Buning, C., Genschel, J., Kling, K., Herrmann, D., Dignass, A., Kuechler, I., Krueger, S., Schmidt, H. H.-J., Lochs, H. <strong>Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation?</strong> Gut 55: 342-347, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16000642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16000642</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16000642[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/10.1136/gut.2005.065557" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16000642">Buhner et al. (2006)</a> studied 128 patients with quiescent CD, 129 first-degree relatives, 66 nonrelated household members, and 96 healthy controls. There were 3 main findings. Healthy first-degree relatives of patients with CD showed increased permeability in contrast with unrelated household members and controls. Secondly, the prevalence of the CARD15 3020insC mutation was similar in first-degree relatives and CD patients and higher compared with controls. Thirdly, in healthy first-degree relatives, high mucosal permeability and the presence of a CARD15 3020insC mutation were significantly associated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16000642" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Yao Syndrome, Susceptibility to</em></strong></p><p>
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Among 54 patients with multisystem inflammatory disease and variants in the NOD2 gene, or Yao syndrome (YAOS; <a href="/entry/617321">617321</a>), <a href="#60" class="mim-tip-reference" title="Yao, Q., Shen, M., McDonald, C., Lacbawan, F., Moran, R., Shen, B. <strong>NOD2-associated autoinflammatory disease: a large cohort study.</strong> Rheumatology 54: 1904-1912, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26070941/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26070941</a>] [<a href="https://doi.org/10.1093/rheumatology/kev207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26070941">Yao et al. (2015)</a> identified 2 patients who were compound heterozygous for the IVS8+158 variant (<a href="#0007">605956.0007</a>) and the 1007fs mutation in NOD2. The authors noted that it remained unclear whether these variants were causative or served as markers indirectly associated with the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26070941" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs2066845 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2066845;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/rs2066845?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=rs2066845" 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=rs2066845" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><strong><em>Inflammatory Bowel Disease 1 (Crohn Disease), Susceptibility to</em></strong></p><p>
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<a href="#19" class="mim-tip-reference" title="Hugot, J.-P., Chamaillard, M., Zouali, H., Lesage, S., Cezard, J.-P., Belaiche, J., Almer, S., Tysk, C., O'Morain, C. A., Gassull, M., Binder, V., Finkel, Y., and 8 others. <strong>Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.</strong> Nature 411: 599-603, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11385576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11385576</a>] [<a href="https://doi.org/10.1038/35079107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11385576">Hugot et al. (2001)</a> identified a mutation leading to a gly881-to-arg (GLY881ARG) substitution in the NOD2 gene that was associated with an increased susceptibility to Crohn disease (IBD1; <a href="/entry/266600">266600</a>). The allele frequency of this mutation was 0.11 among Crohn disease patients, 0.03 among ulcerative colitis (IBD1; <a href="/entry/266600">266600</a>) patients, and 0.04 among unaffected controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11385576" 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>This mutation was designated GLY908ARG in the studies of <a href="#39" class="mim-tip-reference" title="Ogura, Y., Bonen, D. K., Inohara, N., Nicolae, D. L., Chen, F. F., Ramos, R., Britton, H., Moran, T., Karaliuskas, R., Duerr, R. H., Achkar, J.-P., Brant, S. R., Bayless, T. M., Kirschner, B. S., Hanauer, S. B., Nunez, G., Cho, J. H. <strong>A frameshift mutation in Nod2 associated with susceptibility to Crohn's disease.</strong> Nature 411: 603-606, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11385577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11385577</a>] [<a href="https://doi.org/10.1038/35079114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11385577">Ogura et al. (2001)</a> and <a href="#55" class="mim-tip-reference" title="Vermeire, S., Wild, G., Kocher, K., Cousineau, J., Dufresne, L., Bitton, A., Langelier, D., Pare, P., Lapointe, G., Cohen, A., Daly, M. J., Rioux, J. D. <strong>CARD15 genetic variation in a Quebec population: prevalence, genotype-phenotype relationship, and haplotype structure.</strong> Am. J. Hum. Genet. 71: 74-83, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12019468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12019468</a>] [<a href="https://doi.org/10.1086/341124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12019468">Vermeire et al. (2002)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11385577+12019468" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Yao Syndrome, Susceptibility to</em></strong></p><p>
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Among 54 patients with multisystem inflammatory disease and variants in the NOD2 gene, or Yao syndrome (YAOS; <a href="/entry/617321">617321</a>), <a href="#60" class="mim-tip-reference" title="Yao, Q., Shen, M., McDonald, C., Lacbawan, F., Moran, R., Shen, B. <strong>NOD2-associated autoinflammatory disease: a large cohort study.</strong> Rheumatology 54: 1904-1912, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26070941/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26070941</a>] [<a href="https://doi.org/10.1093/rheumatology/kev207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26070941">Yao et al. (2015)</a> identified 1 patient who carried 3 NOD2 variants: G908R, R702W (<a href="#0003">605956.0003</a>), and IVS8+158 (<a href="#0007">605956.0007</a>). The authors noted that it remained unclear whether these variants were causative or served as markers indirectly associated with the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26070941" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs2066844 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2066844;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/rs2066844?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=rs2066844" 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=rs2066844" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000203217 OR RCV000365422 OR RCV000416493 OR RCV001535441 OR RCV001781186 OR RCV001810832 OR RCV002262557 OR RCV002512783" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000203217, RCV000365422, RCV000416493, RCV001535441, RCV001781186, RCV001810832, RCV002262557, RCV002512783" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000203217...</a>
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<p><strong><em>Inflammatory Bowel Disease 1 (Crohn Disease), Susceptibility to</em></strong></p><p>
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<a href="#19" class="mim-tip-reference" title="Hugot, J.-P., Chamaillard, M., Zouali, H., Lesage, S., Cezard, J.-P., Belaiche, J., Almer, S., Tysk, C., O'Morain, C. A., Gassull, M., Binder, V., Finkel, Y., and 8 others. <strong>Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.</strong> Nature 411: 599-603, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11385576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11385576</a>] [<a href="https://doi.org/10.1038/35079107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11385576">Hugot et al. (2001)</a> identified a mutation leading to an arg675-to-trp (ARG675TRP) substitution in the NOD2 gene that was associated with increased susceptibility to Crohn disease (IBD1; <a href="/entry/266600">266600</a>). The allele frequency of this mutation was 0.06 among Crohn disease patients, 0.01 among unaffected controls, and it was not present among ulcerative colitis patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11385576" 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>This mutation was designated ARG702TRP in the study of <a href="#55" class="mim-tip-reference" title="Vermeire, S., Wild, G., Kocher, K., Cousineau, J., Dufresne, L., Bitton, A., Langelier, D., Pare, P., Lapointe, G., Cohen, A., Daly, M. J., Rioux, J. D. <strong>CARD15 genetic variation in a Quebec population: prevalence, genotype-phenotype relationship, and haplotype structure.</strong> Am. J. Hum. Genet. 71: 74-83, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12019468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12019468</a>] [<a href="https://doi.org/10.1086/341124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12019468">Vermeire et al. (2002)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12019468" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Yao Syndrome, Susceptibility to</em></strong></p><p>
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In 4 unrelated patients with multisystem autoinflammatory disease (YAOS; <a href="/entry/617321">617321</a>), <a href="#62" class="mim-tip-reference" title="Yao, Q., Zhou, L., Cusumano, P., Bose, N., Piliang, M., Jayakar, B., Su, L.-C., Shen, B. <strong>A new category of autoinflammatory disease associated with NOD2 gene mutations.</strong> Arthritis Res. Ther. 13: R148, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21914217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21914217</a>] [<a href="https://doi.org/10.1186/ar3462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21914217">Yao et al. (2011)</a> identified heterozygosity for the R702W mutation in the NOD2 gene. The patients also carried the known intronic variant IVS8+158 in NOD2 (<a href="#0007">605956.0007</a>). <a href="#62" class="mim-tip-reference" title="Yao, Q., Zhou, L., Cusumano, P., Bose, N., Piliang, M., Jayakar, B., Su, L.-C., Shen, B. <strong>A new category of autoinflammatory disease associated with NOD2 gene mutations.</strong> Arthritis Res. Ther. 13: R148, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21914217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21914217</a>] [<a href="https://doi.org/10.1186/ar3462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21914217">Yao et al. (2011)</a> stated that the clinical relevance of these mutations remained to be determined, and that this disease might be genetically complex rather than mendelian. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21914217" 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 a cohort of 22 patients with autoinflammatory disease that included the 7 patients previously studied by <a href="#62" class="mim-tip-reference" title="Yao, Q., Zhou, L., Cusumano, P., Bose, N., Piliang, M., Jayakar, B., Su, L.-C., Shen, B. <strong>A new category of autoinflammatory disease associated with NOD2 gene mutations.</strong> Arthritis Res. Ther. 13: R148, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21914217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21914217</a>] [<a href="https://doi.org/10.1186/ar3462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21914217">Yao et al. (2011)</a>, <a href="#61" class="mim-tip-reference" title="Yao, Q., Su, L.-C., Tomecki, K. J., Zhou, L., Jayakar, B., Shen, B. <strong>Dermatitis as a characteristic phenotype of a new autoinflammatory disease associated with NOD2 mutations.</strong> J. Am. Acad. Derm. 68: 624-631, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23102769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23102769</a>] [<a href="https://doi.org/10.1016/j.jaad.2012.09.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23102769">Yao et al. (2013)</a> screened the NOD2 gene and identified heterozygosity for the R702W variant in 8 patients, all but 1 of whom also carried the IVS8+158 variant. Five of the 8 patients had varying degrees of gastrointestinal symptoms, but <a href="#61" class="mim-tip-reference" title="Yao, Q., Su, L.-C., Tomecki, K. J., Zhou, L., Jayakar, B., Shen, B. <strong>Dermatitis as a characteristic phenotype of a new autoinflammatory disease associated with NOD2 mutations.</strong> J. Am. Acad. Derm. 68: 624-631, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23102769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23102769</a>] [<a href="https://doi.org/10.1016/j.jaad.2012.09.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23102769">Yao et al. (2013)</a> found no evidence of Crohn disease or ulcerative colitis after extensive evaluation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21914217+23102769" 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>Among 54 patients with multisystem inflammatory disease and variants in the NOD2 gene, <a href="#60" class="mim-tip-reference" title="Yao, Q., Shen, M., McDonald, C., Lacbawan, F., Moran, R., Shen, B. <strong>NOD2-associated autoinflammatory disease: a large cohort study.</strong> Rheumatology 54: 1904-1912, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26070941/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26070941</a>] [<a href="https://doi.org/10.1093/rheumatology/kev207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26070941">Yao et al. (2015)</a> identified 14 patients who were compound heterozygous for IVS8+158 and the R702W variant. The authors noted that it remained unclear whether these variants were causative or served as markers indirectly associated with the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26070941" 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 affected members of 2 families with Blau syndrome (BLAUS; <a href="/entry/186580">186580</a>), <a href="#34" class="mim-tip-reference" title="Miceli-Richard, C., Lesage, S., Rybojad, M., Prieur, A.-M., Manouvrier-Hanu, S., Hafner, R., Chamaillard, M., Zouali, H., Thomas, G., Hugot, J.-P. <strong>CARD15 mutations in Blau syndrome.</strong> Nature Genet. 29: 19-20, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11528384/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11528384</a>] [<a href="https://doi.org/10.1038/ng720" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11528384">Miceli-Richard et al. (2001)</a> found a 1001G-A transition in the NOD2 gene, resulting in an arg334-to-gln (R334Q) amino acid change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11528384" 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 proband and his father with Blau syndrome (BLAUS; <a href="/entry/186580">186580</a>), <a href="#34" class="mim-tip-reference" title="Miceli-Richard, C., Lesage, S., Rybojad, M., Prieur, A.-M., Manouvrier-Hanu, S., Hafner, R., Chamaillard, M., Zouali, H., Thomas, G., Hugot, J.-P. <strong>CARD15 mutations in Blau syndrome.</strong> Nature Genet. 29: 19-20, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11528384/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11528384</a>] [<a href="https://doi.org/10.1038/ng720" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11528384">Miceli-Richard et al. (2001)</a> found a 1405C-T transition in the NOD2 gene, resulting in a leu469-to-phe (L469F) amino acid change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11528384" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104895462 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104895462;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104895462" 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=rs104895462" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a family with Blau syndrome (BLAUS; <a href="/entry/186580">186580</a>), <a href="#34" class="mim-tip-reference" title="Miceli-Richard, C., Lesage, S., Rybojad, M., Prieur, A.-M., Manouvrier-Hanu, S., Hafner, R., Chamaillard, M., Zouali, H., Thomas, G., Hugot, J.-P. <strong>CARD15 mutations in Blau syndrome.</strong> Nature Genet. 29: 19-20, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11528384/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11528384</a>] [<a href="https://doi.org/10.1038/ng720" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11528384">Miceli-Richard et al. (2001)</a> found a 1000C-T transition in the NOD2 gene, resulting in an arg334-to-trp (R334W) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11528384" 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 a 27-year-old Japanese man who had dermatitis and arthritis in infancy and later developed severe eye inflammation, persistent low-grade fever, and camptodactyly, <a href="#20" class="mim-tip-reference" title="Kanazawa, N., Matsushima, S., Kambe, N., Tachibana, T., Nagai, S., Miyachi, Y. <strong>Presence of a sporadic case of systemic granulomatosis syndrome with a CARD15 mutation.</strong> J. Invest. Derm. 122: 851-852, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15086578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15086578</a>] [<a href="https://doi.org/10.1111/j.0022-202X.2004.22341.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15086578">Kanazawa et al. (2004)</a> identified heterozygosity for the R334W mutation in the NOD2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15086578" 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 4 Japanese patients with early-onset sarcoidosis (Blau syndrome), including a patient originally reported by <a href="#45" class="mim-tip-reference" title="Sakurai, Y., Nakajima, M., Kamisue, S., Nishimura, Y., Ueda, T., Miyagawa, S., Hara, T., Yoshioka, A. <strong>Preschool sarcoidosis mimicking juvenile rheumatoid arthritis: the significance of gallium scintigraphy and skin biopsy in the differential diagnosis.</strong> Acta Paediatr. Jpn. 39: 74-78, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9124059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9124059</a>] [<a href="https://doi.org/10.1111/j.1442-200x.1997.tb03560.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9124059">Sakurai et al. (1997)</a> and the 27-year-old man previously studied by <a href="#20" class="mim-tip-reference" title="Kanazawa, N., Matsushima, S., Kambe, N., Tachibana, T., Nagai, S., Miyachi, Y. <strong>Presence of a sporadic case of systemic granulomatosis syndrome with a CARD15 mutation.</strong> J. Invest. Derm. 122: 851-852, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15086578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15086578</a>] [<a href="https://doi.org/10.1111/j.0022-202X.2004.22341.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15086578">Kanazawa et al. (2004)</a>, <a href="#21" class="mim-tip-reference" title="Kanazawa, N., Okafuji, I., Kambe, N., Nishikomori, R., Nakata-Hizume, M., Nagai, S., Fuji, A., Yuasa, T., Manki, A., Sakurai, Y., Nakajima, M., Kobayashi, H., Fujiwara, I., Tsutsumi, H., Utani, A., Nishigori, C., Heike, T., Nakahata, T., Miyachi, Y. <strong>Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappa-B activation: common genetic etiology with Blau syndrome.</strong> Blood 105: 1195-1197, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15459013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15459013</a>] [<a href="https://doi.org/10.1182/blood-2004-07-2972" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15459013">Kanazawa et al. (2005)</a> identified heterozygosity for the R334W mutation in the NOD2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15086578+15459013+9124059" 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 a 63-year-old man with Blau syndrome, who exhibited severe camptodactyly and bilateral leg ulcerations, <a href="#8" class="mim-tip-reference" title="Dhondt, V., Hofman, S., Dahan, K., Beele, H. <strong>Leg ulcers: a new symptom of Blau syndrome?</strong> Europ. J. Derm. 18: 635-637, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18955195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18955195</a>] [<a href="https://doi.org/10.1684/ejd.2008.0510" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18955195">Dhondt et al. (2008)</a> identified heterozygosity for the R334W mutation in the central nucleotide-binding oligomerization domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18955195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs5743289 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs5743289;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/rs5743289?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=rs5743289" 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=rs5743289" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000416486 OR RCV000416489 OR RCV000960463 OR RCV001029749 OR RCV001781187 OR RCV005208820" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000416486, RCV000416489, RCV000960463, RCV001029749, RCV001781187, RCV005208820" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000416486...</a>
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In 112 Ashkenazi Jewish patients with Crohn disease (IBD1; <a href="/entry/266600">266600</a>), <a href="#48" class="mim-tip-reference" title="Sugimura, K., Taylor, K. D., Lin, Y., Hang, T., Wang, D., Tang, Y.-M., Fischel-Ghodsian, N., Targan, S. R., Rotter, J. I., Yang, H. <strong>A novel NOD2/CARD15 haplotype conferring risk for Crohn disease in Ashkenazi Jews.</strong> Am. J. Hum. Genet. 72: 509-518, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12577202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12577202</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12577202[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/10.1086/367848" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12577202">Sugimura et al. (2003)</a> found a novel disease-predisposing variant in the NOD2 gene, IVS8+158, which is a C-to-T mutation in the palindrome sequence in the intron 8 splicing region. The IVS8+158 variant, which the authors designated 'JW1,' occurred on a specific haplotype with a 268S variant, and this combination exhibited a further increased risk (odds ratio = 5.75, p = 0.0005) and the highest population-attributable risk (15.1%) for Crohn disease (CD) among reported disease-predisposing mutations in Jews. However, no association was found between the 268S-JW1 haplotype and disease in 166 non-Jewish white CD patients. <a href="#48" class="mim-tip-reference" title="Sugimura, K., Taylor, K. D., Lin, Y., Hang, T., Wang, D., Tang, Y.-M., Fischel-Ghodsian, N., Targan, S. R., Rotter, J. I., Yang, H. <strong>A novel NOD2/CARD15 haplotype conferring risk for Crohn disease in Ashkenazi Jews.</strong> Am. J. Hum. Genet. 72: 509-518, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12577202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12577202</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12577202[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/10.1086/367848" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12577202">Sugimura et al. (2003)</a> concluded that in Ashkenazi Jews, unrecognized population-specific predisposing factor(s) for CD exist on the 268S-JW1 haplotype at the IBD1 locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12577202" 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 a study of 193 Jewish Israeli CD patients, <a href="#23" class="mim-tip-reference" title="Karban, A., Eliakim, R. <strong>Failure to replicate the association of the novel NOD2/CARD15 haplotype (S268P-JW1) to Crohn's disease in the Jewish Israeli population. (Letter)</strong> Gastroenterology 126: 624-625, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14765395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14765395</a>] [<a href="https://doi.org/10.1053/j.gastro.2003.12.026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14765395">Karban and Eliakim (2004)</a> failed to replicate the association of the S268P variant or S268P-IVS+158 combination with Crohn disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14765395" 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="#49" class="mim-tip-reference" title="Tukel, T., Shalata, A., Present, D., Rachmilewitz, D., Mayer, L., Grant, D., Risch, N., Desnick, R. J. <strong>Crohn disease: frequency and nature of CARD15 mutations in Ashkenazi and Sephardi/Oriental Jewish families.</strong> Am. J. Hum. Genet. 74: 623-636, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15024686/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15024686</a>] [<a href="https://doi.org/10.1086/382226" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15024686">Tukel et al. (2004)</a> assessed the haplotypes and allele frequencies of the common NOD2 mutations and variants in 219 members of 50 Ashkenazi Jewish and 53 members of 10 Sephardi/Oriental Jewish multiplex families with CD, in 36 Ashkenazi Jewish patients with sporadic CD, and in 246 Ashkenazi and 82 Sephardi/Oriental Jewish controls, and found no evidence for increased risk associated with the IVS8+158 variant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15024686" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Blau Syndrome</em></strong></p><p>
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In a 9-month-old Caucasian boy with Blau syndrome (BLAUS; <a href="/entry/186580">186580</a>), <a href="#1" class="mim-tip-reference" title="Borzutzky, A., Fried, A., Chou, J., Bonilla, F. A., Kim, S., Dedeoglu, F. <strong>NOD2-associated diseases: bridging innate immunity and autoinflammation.</strong> Clin. Immun. 134: 251-261, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19467619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19467619</a>] [<a href="https://doi.org/10.1016/j.clim.2009.05.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19467619">Borzutzky et al. (2010)</a> identified heterozygosity for the IVS8+158 variant in the NOD2 gene. <a href="#1" class="mim-tip-reference" title="Borzutzky, A., Fried, A., Chou, J., Bonilla, F. A., Kim, S., Dedeoglu, F. <strong>NOD2-associated diseases: bridging innate immunity and autoinflammation.</strong> Clin. Immun. 134: 251-261, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19467619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19467619</a>] [<a href="https://doi.org/10.1016/j.clim.2009.05.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19467619">Borzutzky et al. (2010)</a> stated that this was the first reported case of gastrointestinal granulomas in a patient with early-onset sarcoidosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19467619" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Yao Syndrome, Susceptibility to</em></strong></p><p>
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In 7 unrelated patients with multisystem autoinflammatory disease (YAOS; <a href="/entry/617321">617321</a>), <a href="#62" class="mim-tip-reference" title="Yao, Q., Zhou, L., Cusumano, P., Bose, N., Piliang, M., Jayakar, B., Su, L.-C., Shen, B. <strong>A new category of autoinflammatory disease associated with NOD2 gene mutations.</strong> Arthritis Res. Ther. 13: R148, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21914217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21914217</a>] [<a href="https://doi.org/10.1186/ar3462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21914217">Yao et al. (2011)</a> identified heterozygosity for the IVS8+158 variant in the NOD2 gene. Four of the patients also carried the R702W mutation in NOD2 (<a href="#0003">605956.0003</a>). <a href="#62" class="mim-tip-reference" title="Yao, Q., Zhou, L., Cusumano, P., Bose, N., Piliang, M., Jayakar, B., Su, L.-C., Shen, B. <strong>A new category of autoinflammatory disease associated with NOD2 gene mutations.</strong> Arthritis Res. Ther. 13: R148, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21914217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21914217</a>] [<a href="https://doi.org/10.1186/ar3462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21914217">Yao et al. (2011)</a> stated that the clinical relevance of these gene mutations remained to be determined, and that this disease might be genetically complex rather than mendelian. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21914217" 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 22 patients with autoinflammatory disease, including the 7 patients previously studied by <a href="#62" class="mim-tip-reference" title="Yao, Q., Zhou, L., Cusumano, P., Bose, N., Piliang, M., Jayakar, B., Su, L.-C., Shen, B. <strong>A new category of autoinflammatory disease associated with NOD2 gene mutations.</strong> Arthritis Res. Ther. 13: R148, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21914217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21914217</a>] [<a href="https://doi.org/10.1186/ar3462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21914217">Yao et al. (2011)</a>, <a href="#61" class="mim-tip-reference" title="Yao, Q., Su, L.-C., Tomecki, K. J., Zhou, L., Jayakar, B., Shen, B. <strong>Dermatitis as a characteristic phenotype of a new autoinflammatory disease associated with NOD2 mutations.</strong> J. Am. Acad. Derm. 68: 624-631, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23102769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23102769</a>] [<a href="https://doi.org/10.1016/j.jaad.2012.09.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23102769">Yao et al. (2013)</a> screened the NOD2 gene and found that all carried at least 1 variant: 21 had the IVS8+158 variant, and 8 had the R702W variant. <a href="#61" class="mim-tip-reference" title="Yao, Q., Su, L.-C., Tomecki, K. J., Zhou, L., Jayakar, B., Shen, B. <strong>Dermatitis as a characteristic phenotype of a new autoinflammatory disease associated with NOD2 mutations.</strong> J. Am. Acad. Derm. 68: 624-631, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23102769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23102769</a>] [<a href="https://doi.org/10.1016/j.jaad.2012.09.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23102769">Yao et al. (2013)</a> noted that the allele frequency of the IVS8+158 variant in the healthy white population had been estimated to be approximately 15% by <a href="#48" class="mim-tip-reference" title="Sugimura, K., Taylor, K. D., Lin, Y., Hang, T., Wang, D., Tang, Y.-M., Fischel-Ghodsian, N., Targan, S. R., Rotter, J. I., Yang, H. <strong>A novel NOD2/CARD15 haplotype conferring risk for Crohn disease in Ashkenazi Jews.</strong> Am. J. Hum. Genet. 72: 509-518, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12577202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12577202</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12577202[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/10.1086/367848" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12577202">Sugimura et al. (2003)</a>, whereas in an aggregated cohort of 41 patients tested by <a href="#61" class="mim-tip-reference" title="Yao, Q., Su, L.-C., Tomecki, K. J., Zhou, L., Jayakar, B., Shen, B. <strong>Dermatitis as a characteristic phenotype of a new autoinflammatory disease associated with NOD2 mutations.</strong> J. Am. Acad. Derm. 68: 624-631, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23102769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23102769</a>] [<a href="https://doi.org/10.1016/j.jaad.2012.09.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23102769">Yao et al. (2013)</a> for IVS8+158, the variant was detected in approximately 55% of patients (p less than 0.001), all of whom were non-Jewish. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12577202+21914217+23102769" 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="#60" class="mim-tip-reference" title="Yao, Q., Shen, M., McDonald, C., Lacbawan, F., Moran, R., Shen, B. <strong>NOD2-associated autoinflammatory disease: a large cohort study.</strong> Rheumatology 54: 1904-1912, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26070941/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26070941</a>] [<a href="https://doi.org/10.1093/rheumatology/kev207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26070941">Yao et al. (2015)</a> genotyped 143 patients with symptoms suggestive of Yao syndrome for NOD2 variants and identified 54 patients who fulfilled criteria for the disorder, including the presence of NOD2 variants. The IVS8+158 variant was detected in 46 of the 54 patients, including 30 who carried only IVS8+158 and 18 who also carried other known variants, including R702W, 3020insC (<a href="#0001">605956.0001</a>), and G908R (<a href="#0002">605956.0002</a>). In addition, 9 other rare NOD2 variants were detected in 13 of the patients. <a href="#60" class="mim-tip-reference" title="Yao, Q., Shen, M., McDonald, C., Lacbawan, F., Moran, R., Shen, B. <strong>NOD2-associated autoinflammatory disease: a large cohort study.</strong> Rheumatology 54: 1904-1912, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26070941/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26070941</a>] [<a href="https://doi.org/10.1093/rheumatology/kev207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26070941">Yao et al. (2015)</a> noted that it remained unclear whether these variants were causative or served as markers indirectly associated with the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26070941" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104895472 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104895472;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104895472" 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=rs104895472" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 32-year-old woman with Blau syndrome (BLAUS; <a href="/entry/186580">186580</a>), originally described by <a href="#46" class="mim-tip-reference" title="Shimomura, Y., Tada, R., Yamamoto, Y., Yuasa, T. <strong>Ocular sarcoidosis in a 7-year-old child.</strong> Jpn. J. Clin. Ophthal. 36: 109-112, 1982."None>Shimomura et al. (1982)</a> as a case of 'ocular sarcoidosis,' <a href="#21" class="mim-tip-reference" title="Kanazawa, N., Okafuji, I., Kambe, N., Nishikomori, R., Nakata-Hizume, M., Nagai, S., Fuji, A., Yuasa, T., Manki, A., Sakurai, Y., Nakajima, M., Kobayashi, H., Fujiwara, I., Tsutsumi, H., Utani, A., Nishigori, C., Heike, T., Nakahata, T., Miyachi, Y. <strong>Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappa-B activation: common genetic etiology with Blau syndrome.</strong> Blood 105: 1195-1197, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15459013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15459013</a>] [<a href="https://doi.org/10.1182/blood-2004-07-2972" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15459013">Kanazawa et al. (2005)</a> identified heterozygosity for a 1487A-T transversion in the NOD2 gene, resulting in a his496-to-leu (H496L) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15459013" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs104895476 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104895476;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/rs104895476?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=rs104895476" 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=rs104895476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000416482 OR RCV003764528" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000416482, RCV003764528" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000416482...</a>
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<p>In a 16-year-old girl with Blau syndrome (BLAUS; <a href="/entry/186580">186580</a>), originally reported by <a href="#50" class="mim-tip-reference" title="Ukae, S., Tsutsumi, H., Adachi, N., Takahashi, H., Kato, F., Chiba, S. <strong>Preschool sarcoidosis manifesting as juvenile rheumatoid arthritis: a case report and a review of the literature of Japanese cases.</strong> Acta Paediatr. Jpn. 36: 515-518, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7825454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7825454</a>] [<a href="https://doi.org/10.1111/j.1442-200x.1994.tb03237.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7825454">Ukae et al. (1994)</a> as a case of 'preschool sarcoidosis,' <a href="#21" class="mim-tip-reference" title="Kanazawa, N., Okafuji, I., Kambe, N., Nishikomori, R., Nakata-Hizume, M., Nagai, S., Fuji, A., Yuasa, T., Manki, A., Sakurai, Y., Nakajima, M., Kobayashi, H., Fujiwara, I., Tsutsumi, H., Utani, A., Nishigori, C., Heike, T., Nakahata, T., Miyachi, Y. <strong>Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappa-B activation: common genetic etiology with Blau syndrome.</strong> Blood 105: 1195-1197, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15459013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15459013</a>] [<a href="https://doi.org/10.1182/blood-2004-07-2972" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15459013">Kanazawa et al. (2005)</a> identified 2 missense mutations in the CARD15 gene: a 1146C-G transversion, resulting in an asp382-to-glu (D382E) substitution, and a 1834G-A transition, resulting in an ala612-to-thr (A612T) substitution (<a href="#0010">605956.0010</a>). <a href="#21" class="mim-tip-reference" title="Kanazawa, N., Okafuji, I., Kambe, N., Nishikomori, R., Nakata-Hizume, M., Nagai, S., Fuji, A., Yuasa, T., Manki, A., Sakurai, Y., Nakajima, M., Kobayashi, H., Fujiwara, I., Tsutsumi, H., Utani, A., Nishigori, C., Heike, T., Nakahata, T., Miyachi, Y. <strong>Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappa-B activation: common genetic etiology with Blau syndrome.</strong> Blood 105: 1195-1197, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15459013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15459013</a>] [<a href="https://doi.org/10.1182/blood-2004-07-2972" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15459013">Kanazawa et al. (2005)</a> noted that the A612T mutation, which previously had been detected in a patient with Crohn disease (IBD1; <a href="/entry/266600">266600</a>) by <a href="#29" class="mim-tip-reference" title="Lesage, S., Zouali, H., Cezard, J.-P., EPWG-IBD Group, Colombel, J.-F., EPIMAD Group, Belaiche, J., GETAID Group, Almer, S., Tysk, C., O'Morain, C., Gassull, M., Binder, V., Finkel, Y., Modigliani, R., Gower-Rousseau, C., Macry, J., Merlin, F., Chamaillard, M., Jannot, A.-S., Thomas, G., Hugot, J.-P. <strong>CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease.</strong> Am. J. Hum. Genet. 70: 845-857, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11875755/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11875755</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11875755[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/10.1086/339432" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11875755">Lesage et al. (2002)</a>, was also found in heterozygosity in 1 of 100 Japanese controls. <a href="#15" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. February 22, 2017."None>Hamosh (2017)</a> noted that the allelic frequency of the A612T mutation in the ExAC database (February 22, 2017) suggests that this variant is not pathogenic. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15459013+7825454+11875755" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs104895438 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104895438;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/rs104895438?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=rs104895438" 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=rs104895438" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000328692 OR RCV001280996 OR RCV001781188 OR RCV002512787 OR RCV003421904" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000328692, RCV001280996, RCV001781188, RCV002512787, RCV003421904" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000328692...</a>
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<p>This variant, previously designated BLAU SYNDROME, has been reclassified based on a review of the ExAC database by <a href="#15" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. February 22, 2017."None>Hamosh (2017)</a>.</p><p><a href="#21" class="mim-tip-reference" title="Kanazawa, N., Okafuji, I., Kambe, N., Nishikomori, R., Nakata-Hizume, M., Nagai, S., Fuji, A., Yuasa, T., Manki, A., Sakurai, Y., Nakajima, M., Kobayashi, H., Fujiwara, I., Tsutsumi, H., Utani, A., Nishigori, C., Heike, T., Nakahata, T., Miyachi, Y. <strong>Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappa-B activation: common genetic etiology with Blau syndrome.</strong> Blood 105: 1195-1197, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15459013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15459013</a>] [<a href="https://doi.org/10.1182/blood-2004-07-2972" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15459013">Kanazawa et al. (2005)</a> reported an ala612-to-thr (A612T) substitution in the CARD15 gene in compound heterozygous state with an asp382-to-glu (D382E; <a href="#0009">605956.0009</a>) substitution in a patient with Blau syndrome (BLAUS; <a href="/entry/186580">186580</a>). They noted that the A612T mutation was also found in heterozygosity in 1 of 100 Japanese controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15459013" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. February 22, 2017."None>Hamosh (2017)</a> found the A nucleotide (resulting in thr at residue 612) in 77 of 121,180 alleles and in homozygosity in 1 individual in the ExAC database (February 22, 2017), suggesting that the variant is not pathogenic.</p>
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NOD2, GLU383LYS
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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> rs104895477 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104895477;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/rs104895477?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=rs104895477" 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=rs104895477" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000004966 OR RCV002512788" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004966, RCV002512788" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004966...</a>
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<p>In a mother and daughter with Blau syndrome (BLAUS; <a href="/entry/186580">186580</a>), <a href="#51" class="mim-tip-reference" title="van Duist, M. M., Albrecht, M., Podswiadek, M., Giachino, D., Lengauer, T., Punzi, L., De Marchi, M. <strong>A new CARD15 mutation in Blau syndrome.</strong> Europ. J. Hum. Genet. 13: 742-747, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15812565/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15812565</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15812565">van Duist et al. (2005)</a> identified a heterozygous 1147G-A transition in exon 4 of the CARD15 gene, resulting in a glu383-to-lys (E383K) substitution. The mutation is in a highly conserved region in the central nucleotide-binding NACHT domain and may result in increased signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15812565" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 INFLAMMATORY BOWEL DISEASE 1 (CROHN DISEASE), SUSCEPTIBILITY TO</strong>
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<div style="float: left;">
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NOD2, 1-BP INS, 3016C (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2066847;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2066847</a>)
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000334899 OR RCV000389442 OR RCV000416485 OR RCV001529584 OR RCV001701717 OR RCV001781184 OR RCV002260960 OR RCV002468553 OR RCV002512781 OR RCV003224089" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000334899, RCV000389442, RCV000416485, RCV001529584, RCV001701717, RCV001781184, RCV002260960, RCV002468553, RCV002512781, RCV003224089" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000334899...</a>
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<p><a href="#31" class="mim-tip-reference" title="MacArthur, D. G., Balasubramanian, S., Frankish, A., Huang, N., Morris, J., Walter, K., Jostins, L., Habegger, L., Pickrell, J. K., Montgomery, S. B., Albers, C. A., Zhang, Z. D., and 40 others. <strong>A systematic survey of loss-of-function variants in human protein-coding genes.</strong> Science 335: 823-828, 2012. Note: Erratum: Science 336: 296 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22344438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22344438</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22344438[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1215040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22344438">MacArthur et al. (2012)</a> reported a 1-bp insertion (3016_3017insC) in the NOD2 gene, leading to a frameshift, that was associated with Crohn disease (IBD1; <a href="/entry/266600">266600</a>). The genomewide-significant imputed P value was 1.78 x 10(-14), just 2 orders of magnitude more significant than the best tag SNP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22344438" 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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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-font">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
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<a id="Borzutzky2010" class="mim-anchor"></a>
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Borzutzky, A., Fried, A., Chou, J., Bonilla, F. A., Kim, S., Dedeoglu, F.
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<strong>NOD2-associated diseases: bridging innate immunity and autoinflammation.</strong>
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Clin. Immun. 134: 251-261, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19467619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19467619</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19467619" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.clim.2009.05.005" target="_blank">Full Text</a>]
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<a id="Brain2013" class="mim-anchor"></a>
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Brain, O., Owens, B. M. J., Pichulik, T., Allan, P., Khatamzas, E., Leslie, A., Steevels, T., Sharma, S., Mayer, A., Catuneanu, A. M., Morton, V., Sun, M.-Y., Jewell, D., Coccia, M., Harrison, O., Maloy, K., Schonefeldt, S., Bornschein, S., Liston, A., Simmons, A.
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<strong>The intracellular sensor NOD2 induces microRNA-29 expression in human dendritic cells to limit IL-23 release.</strong>
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Immunity 39: 521-536, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24054330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24054330</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24054330" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.immuni.2013.08.035" target="_blank">Full Text</a>]
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<a id="Buhner2006" class="mim-anchor"></a>
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Buhner, S., Buning, C., Genschel, J., Kling, K., Herrmann, D., Dignass, A., Kuechler, I., Krueger, S., Schmidt, H. H.-J., Lochs, H.
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<strong>Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation?</strong>
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Gut 55: 342-347, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16000642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16000642</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16000642[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=16000642" 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/10.1136/gut.2005.065557" target="_blank">Full Text</a>]
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<a id="Chamaillard2003" class="mim-anchor"></a>
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Chamaillard, M., Philpott, D., Girardin, S. E., Zouali, H., Lesage, S., Chareyre, F., Bui, T. H., Giovannini, M., Zaehringer, U., Penard-Lacronique, V., Sansonetti, P. J., Hugot, J.-P., Thomas, G.
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<strong>Gene-environment interaction modulated by allelic heterogeneity in inflammatory diseases.</strong>
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Proc. Nat. Acad. Sci. 100: 3455-3460, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12626759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12626759</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12626759[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=12626759" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0530276100" target="_blank">Full Text</a>]
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<a id="Chu2016" class="mim-anchor"></a>
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Chu, H., Khosravi, A., Kusumawardhani, I. P., Kwon, A. H. K., Vasconcelos, A. C., Cunha, L. D., Mayer, A. E., Shen, Y., Wu, W.-L., Kambal, A., Targan, S. R., Xavier, R. J., Ernst, P. B., Green, D. R., McGovern, D. P. B., Virgin, H. W., Mazmanian, S. K.
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<strong>Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease.</strong>
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Science 352: 1116-1120, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27230380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27230380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27230380[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=27230380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.aad9948" target="_blank">Full Text</a>]
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<a id="Cooney2010" class="mim-anchor"></a>
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Cooney, R., Baker, J., Brain, O., Danis, B., Pichulik, T., Allan, P., Ferguson, D. J. P., Campbell, B. J., Jewell, D., Simmons, A.
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<strong>NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation.</strong>
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Nature Med. 16: 90-97, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19966812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19966812</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19966812" 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/nm.2069" target="_blank">Full Text</a>]
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Croucher, P. J. P., Mascheretti, S., Hampe, J., Huse, K., Frenzel, H., Stoll, M., Lu, T., Nikolaus, S., Yang, S.-K., Krawczak, M., Kim, W. H., Schreiber, S.
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<strong>Haplotype structure and association to Crohn's disease of CARD15 mutations in two ethnically divergent populations.</strong>
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Europ. J. Hum. Genet. 11: 6-16, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12529700/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12529700</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12529700" 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.ejhg.5200897" target="_blank">Full Text</a>]
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<a id="Dhondt2008" class="mim-anchor"></a>
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<strong>Leg ulcers: a new symptom of Blau syndrome?</strong>
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[<a href="https://doi.org/10.1684/ejd.2008.0510" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.4049/jimmunol.181.10.7157" target="_blank">Full Text</a>]
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</p>
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[<a href="https://doi.org/10.1002/ajmg.a.20209" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nm.2391" target="_blank">Full Text</a>]
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<strong>Analysis of the CARD15 variants R702W, G908R and L1007fs in Italian IBD patients.</strong>
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[<a href="https://doi.org/10.1038/sj.ejhg.5201130" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1097/00002281-200207000-00005" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000267429.89675.03" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/S0140-6736(00)05063-7" target="_blank">Full Text</a>]
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Hampe, J., Grebe, J., Nikolaus, S., Solberg, C., Croucher, P. J. P., Mascheretti, S., Jahnsen, J., Moum, B., Klump, B., Krawczak, M., Mirza, M. M., Foelsch, U. R., Vatn, M., Schreiber, S.
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[<a href="https://doi.org/10.1016/S0140-6736(02)08590-2" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19541630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19541630</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19541630[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=19541630" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0904958106" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/35079107" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.0022-202X.2004.22341.x" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15459013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15459013</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15459013" 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-2004-07-2972" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12474146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12474146</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12474146[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=12474146" 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/10.1086/345646" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14765395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14765395</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14765395" 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/10.1053/j.gastro.2003.12.026" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15220916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15220916</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15220916" 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/ni1092" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="57" class="mim-anchor"></a>
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<a id="{Wellcome Trust Case Control Consortium}2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wellcome Trust Case Control Consortium.
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<strong>Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.</strong>
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|
Nature 447: 661-678, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17554300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17554300</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17554300[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=17554300" 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/nature05911" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="58" class="mim-anchor"></a>
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<a id="Yamazaki2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yamazaki, K., Takazoe, M., Tanaka, T., Ichimori, T., Nakamura, Y.
|
|
<strong>Absence of mutation in the NOD2/CARD15 gene among 483 Japanese patients with Crohn's disease.</strong>
|
|
J. Hum. Genet. 47: 469-472, 2002. Note: Erratum: J. Hum. Genet. 48: 397 only, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12202985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12202985</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12202985" 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/10.1007/s100380200067" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="59" class="mim-anchor"></a>
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<a id="Yao2022" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
|
|
Yao, Q., Kontzias, A.
|
|
<strong>Expansion of phenotypic and genotypic spectrum in Yao syndrome: a case series.</strong>
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|
J. Clin. Rheum. 28: e156-e160, 2022.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33394828/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33394828</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33394828" 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/10.1097/RHU.0000000000001655" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="60" class="mim-anchor"></a>
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<a id="Yao2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yao, Q., Shen, M., McDonald, C., Lacbawan, F., Moran, R., Shen, B.
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<strong>NOD2-associated autoinflammatory disease: a large cohort study.</strong>
|
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Rheumatology 54: 1904-1912, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26070941/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26070941</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26070941" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/rheumatology/kev207" target="_blank">Full Text</a>]
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<li>
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<a id="61" class="mim-anchor"></a>
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<a id="Yao2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yao, Q., Su, L.-C., Tomecki, K. J., Zhou, L., Jayakar, B., Shen, B.
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<strong>Dermatitis as a characteristic phenotype of a new autoinflammatory disease associated with NOD2 mutations.</strong>
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J. Am. Acad. Derm. 68: 624-631, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23102769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23102769</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23102769" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.jaad.2012.09.025" target="_blank">Full Text</a>]
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<li>
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<a id="62" class="mim-anchor"></a>
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<a id="Yao2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yao, Q., Zhou, L., Cusumano, P., Bose, N., Piliang, M., Jayakar, B., Su, L.-C., Shen, B.
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<strong>A new category of autoinflammatory disease associated with NOD2 gene mutations.</strong>
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Arthritis Res. Ther. 13: R148, 2011. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21914217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21914217</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21914217" 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/10.1186/ar3462" target="_blank">Full Text</a>]
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</ol>
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<br />
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</div>
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<a id="contributors" class="mim-anchor"></a>
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 06/27/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 02/22/2017<br>Marla J. F. O'Neill - updated : 01/31/2017<br>Ada Hamosh - updated : 09/01/2016<br>Matthew B. Gross - updated : 08/11/2016<br>Paul J. Converse - updated : 08/11/2016<br>Paul J. Converse - updated : 9/22/2014<br>Ada Hamosh - updated : 6/2/2014<br>Ada Hamosh - updated : 7/23/2012<br>Ada Hamosh - updated : 2/27/2012<br>Paul J. Converse - updated : 8/5/2011<br>Paul J. Converse - updated : 9/28/2010<br>Paul J. Converse - updated : 2/4/2010<br>Paul J. Converse - updated : 1/7/2010<br>Cassandra L. Kniffin - updated : 6/2/2009<br>Cassandra L. Kniffin - updated : 11/30/2007<br>Patricia A. Hartz - updated : 10/31/2007<br>Ada Hamosh - updated : 7/24/2007<br>Victor A. McKusick - updated : 5/31/2007<br>George E. Tiller - updated : 1/16/2007<br>Marla J. F. O'Neill - updated : 5/24/2006<br>Victor A. McKusick - updated : 1/20/2006<br>Paul J. Converse - updated : 10/27/2005<br>Marla J. F. O'Neill - updated : 9/1/2005<br>Cassandra L. Kniffin - updated : 7/11/2005<br>Victor A. McKusick - updated : 3/21/2005<br>Victor A. McKusick - updated : 3/15/2005<br>Ada Hamosh - updated : 2/25/2005<br>Marla J. F. O'Neill - updated : 5/3/2004<br>George E. Tiller - updated : 4/28/2004<br>Victor A. McKusick - updated : 4/27/2004<br>Victor A. McKusick - updated : 4/21/2004<br>Marla J. F. O'Neill - updated : 4/2/2004<br>Victor A. McKusick - updated : 10/8/2003<br>Victor A. McKusick - updated : 9/5/2003<br>Victor A. McKusick - updated : 5/2/2003<br>Victor A. McKusick - updated : 4/25/2003<br>Victor A. McKusick - updated : 3/3/2003<br>Victor A. McKusick - updated : 2/26/2003<br>Victor A. McKusick - updated : 10/1/2002<br>Victor A. McKusick - updated : 9/24/2002<br>Victor A. McKusick - updated : 9/12/2002<br>Victor A. McKusick - updated : 7/17/2002<br>Victor A. McKusick - updated : 6/26/2002<br>Victor A. McKusick - updated : 4/12/2002<br>Victor A. McKusick - updated : 3/1/2002<br>Victor A. McKusick - updated : 8/23/2001<br>Ada Hamosh - updated : 5/22/2001
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</span>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Paul J. Converse : 5/22/2001
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</span>
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</div>
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</div>
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<a id="editHistory" class="mim-anchor"></a>
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 06/27/2023
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 06/12/2018<br>carol : 04/21/2018<br>alopez : 04/20/2018<br>carol : 02/23/2017<br>carol : 02/22/2017<br>carol : 02/01/2017<br>carol : 01/31/2017<br>carol : 01/31/2017<br>alopez : 09/01/2016<br>mgross : 08/11/2016<br>mgross : 08/11/2016<br>carol : 08/01/2016<br>mcolton : 08/18/2015<br>mgross : 9/30/2014<br>mcolton : 9/22/2014<br>alopez : 6/2/2014<br>alopez : 3/14/2013<br>alopez : 7/24/2012<br>terry : 7/23/2012<br>terry : 6/8/2012<br>terry : 6/8/2012<br>alopez : 5/1/2012<br>alopez : 2/28/2012<br>terry : 2/27/2012<br>mgross : 8/9/2011<br>terry : 8/5/2011<br>mgross : 9/30/2010<br>mgross : 9/30/2010<br>terry : 9/28/2010<br>mgross : 2/15/2010<br>mgross : 2/15/2010<br>terry : 2/4/2010<br>mgross : 1/8/2010<br>mgross : 1/8/2010<br>terry : 1/7/2010<br>wwang : 6/22/2009<br>ckniffin : 6/2/2009<br>alopez : 10/31/2008<br>carol : 8/28/2008<br>carol : 8/14/2008<br>wwang : 12/7/2007<br>ckniffin : 11/30/2007<br>ckniffin : 11/29/2007<br>mgross : 11/1/2007<br>terry : 10/31/2007<br>alopez : 7/24/2007<br>alopez : 6/4/2007<br>terry : 5/31/2007<br>alopez : 5/16/2007<br>wwang : 1/26/2007<br>wwang : 1/23/2007<br>terry : 1/16/2007<br>wwang : 6/1/2006<br>terry : 5/24/2006<br>alopez : 2/15/2006<br>terry : 1/20/2006<br>mgross : 11/7/2005<br>terry : 10/27/2005<br>wwang : 9/1/2005<br>wwang : 7/26/2005<br>ckniffin : 7/11/2005<br>carol : 7/5/2005<br>wwang : 3/23/2005<br>terry : 3/21/2005<br>terry : 3/15/2005<br>wwang : 3/3/2005<br>terry : 2/25/2005<br>terry : 6/28/2004<br>alopez : 5/28/2004<br>carol : 5/5/2004<br>terry : 5/3/2004<br>alopez : 4/28/2004<br>alopez : 4/27/2004<br>tkritzer : 4/22/2004<br>terry : 4/21/2004<br>terry : 4/9/2004<br>tkritzer : 4/7/2004<br>tkritzer : 4/7/2004<br>tkritzer : 4/5/2004<br>terry : 4/2/2004<br>alopez : 10/8/2003<br>alopez : 9/8/2003<br>terry : 9/5/2003<br>tkritzer : 5/9/2003<br>tkritzer : 5/7/2003<br>terry : 5/2/2003<br>terry : 4/25/2003<br>carol : 3/10/2003<br>tkritzer : 3/6/2003<br>terry : 3/3/2003<br>alopez : 2/26/2003<br>terry : 2/26/2003<br>carol : 10/2/2002<br>tkritzer : 10/1/2002<br>tkritzer : 10/1/2002<br>tkritzer : 9/24/2002<br>tkritzer : 9/12/2002<br>tkritzer : 9/12/2002<br>tkritzer : 7/30/2002<br>tkritzer : 7/29/2002<br>tkritzer : 7/26/2002<br>terry : 7/17/2002<br>cwells : 7/9/2002<br>terry : 6/26/2002<br>carol : 5/8/2002<br>alopez : 4/25/2002<br>cwells : 4/17/2002<br>terry : 4/12/2002<br>carol : 3/1/2002<br>terry : 3/1/2002<br>alopez : 11/5/2001<br>alopez : 8/27/2001<br>alopez : 8/27/2001<br>terry : 8/23/2001<br>joanna : 7/3/2001<br>joanna : 7/2/2001<br>mgross : 5/30/2001<br>mgross : 5/30/2001<br>mgross : 5/22/2001<br>mgross : 5/22/2001
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</span>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 605956
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN PROTEIN 2; NOD2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div >
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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CASPASE RECRUITMENT DOMAIN-CONTAINING PROTEIN 15; CARD15
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</span>
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</h4>
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</div>
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<div>
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<br />
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: NOD2</em></strong>
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</span>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 818950005;
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<strong>ICD10CM:</strong> M04.8;
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<div>
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<br />
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 16q12.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 16:50,693,606-50,733,075 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
|
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="3">
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<span class="mim-font">
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16q12.1
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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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{Inflammatory bowel disease 1, Crohn disease}
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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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266600
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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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Multifactorial
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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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<tr>
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<td>
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<span class="mim-font">
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{Yao syndrome}
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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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617321
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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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Multifactorial
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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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<tr>
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<td>
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<span class="mim-font">
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Blau syndrome
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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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186580
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</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>Inflammatory responses are triggered when pattern-recognition receptors (PRRs) detect tissue damage or microbial infection. NOD2 belongs to the nucleotide-binding oligomerization domain (NOD)-like receptor family of PRRs (summary by Keestra-Gounder et al., 2016). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>APAF1 (602233) and NOD1 (605980), also called CARD4, are members of a family of intracellular proteins that contain an N-terminal caspase recruitment domain (CARD), a centrally located nucleotide-binding domain (NBD), and a C-terminal regulatory domain. In the case of APAF1, the C-terminal regulatory domain consists of WD40 repeats, whereas NOD1 has leucine-rich repeats (LRRs). NOD1 promotes apoptosis through nuclear factor kappa-B (NFKB; see 164011) activation and has structural similarity to a class of disease-resistance genes in plants that induce localized cell death at the site of pathogen invasion. By searching a genomic database for NOD1 homologs, followed by 5-prime RACE and RT-PCR, Ogura et al. (2001) obtained cDNAs encoding NOD2. Sequence analysis predicted that the 1,040-amino acid NOD2 protein, which is 34% identical to NOD1, contains 2 N-terminal CARDs fused to a central NBD domain followed by 10 tandem LRRs. Ogura et al. (2001) also identified a NOD2 variant encoding a 1,013-amino acid protein, which they called NOD2B. Northern blot analysis detected 7.0- and 5.5-kb NOD2 transcripts in peripheral blood leukocytes, with little or no expression found in other tissues. RT-PCR analysis revealed expression primarily in monocytes. In contrast, NOD1 and APAF1 are broadly expressed. </p><p>By 5-prime RACE and semiquantitative RT-PCR, King et al. (2007) showed that most human NOD2 transcripts in blood leukocytes and colon are products of an alternative first exon. They concluded that the principal NOD2 protein product lacks 27 previously reported N-terminal amino acids. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>King et al. (2007) identified an alternative first exon that lies within a strong CpG island about 3.5 kb upstream of the canonical first exon of the NOD2 gene. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By analysis of BAC clones, Ogura et al. (2001) determined that the NOD2 gene maps to 16q12 and contains 12 coding exons. </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>Ogura et al. (2001) found that expression of NOD2 or NOD2B resulted in NFKB activation and that mutants lacking the LRRs had enhanced NFKB activation. They determined that both intact CARD domains were necessary and sufficient for IKK-gamma (IKBKG; 300248)- and RICK (RIPK2; 603455)-dependent NFKB activation. Coimmunoprecipitation analysis showed that the CARD domain of RICK interacted with the CARD domains of NOD2. Ogura et al. (2001) proposed that NOD2 serves as an intracellular receptor for bacterial products in monocytes and transduces signals leading to NFKB activation. </p><p>Cooney et al. (2010) showed that activation of NOD2 with muramyldipeptide induced autophagy in dendritic cells (DCs) that required RIPK2, PI3K (see 601232), ATG5 (604261), ATG7 (608760), and ATG16L1 (610767), but not NALP3 (NLRP3; 606416). DCs from Crohn disease (CD; 266600) patients with susceptibility variants in NOD2 (e.g., 1007fs; 605956.0001) or ATG16L1 (T300A; 610767.0001) were deficient in autophagy induction. DCs from CD patients with NOD2 variants also showed reduced localization of bacteria in autophagolysosomes, which could be reversed by treatment with rapamycin. Cooney et al. (2010) concluded that NOD2 influences bacterial degradation and interacts with the major histocompatibility complex class II antigen presentation machinery within DCs, and that ATG16L1 and NOD2 are linked within 1 functional pathway. </p><p>Brain et al. (2013) detected upregulated expression of MIR29A (610782), MIR29B (see 610783), and MIR29C (610784) in human DCs stimulated with NOD2. They found that MIR29 regulated expression of multiple immune mediators. Notably, MIR29 downregulated IL23 by targeting its IL12p40 component directly and its IL23p19 (IL23A; 605580) component indirectly, most likely through a reduction of the transcription factor ATF2 (123811). Dextran sodium sulfate (DSS)-induced colitis was exacerbated in mice lacking Mir29 and was associated with elevated Il23 and Th17 cytokines in intestinal mucosa. DCs from Crohn disease patients expressing NOD2 polymorphisms failed to induce MIR29 after stimulation of pathogen pattern recognition receptors, and these DCs showed enhanced release of IL12p40 on exposure to adherent E. coli. Brain et al. (2013) proposed that loss of MIR29-mediated immune regulation in Crohn disease DCs may contribute to elevated IL23 in patients with the disease. </p><p>Nakamura et al. (2014) showed that 2 endolysosomal peptide transporters, SLC15A3 (610408) and SLC15A4 (615806), are preferentially expressed by dendritic cells, especially after Toll-like receptor (TLR) stimulation. The transporters mediate the egress of bacterially derived components, such as the NOD2 cognate ligand muramyl dipeptide (MDP), and are selectively required for NOD2 responses to endosomally derived MDP. Enhanced expression of the transporters also generates endosomal membrane tubules characteristic of dendritic cells, which further enhanced the NOD2-dependent response to MDP. Finally, sensing required the recruitment of NOD2 and its effector kinase RIPK2 to the endosomal membrane, possibly by forming a complex with SLC15A3 or SLC15A4. Thus, Nakamura et al. (2014) concluded that dendritic cell endosomes are specialized platforms for both the luminal and cytosolic sensing of pathogens. </p><p>Using mouse and human cells, Keestra-Gounder et al. (2016) identified NOD1 and NOD2 as mediators of inflammation induced by endoplasmic reticulum (ER) stress. Induction of ER stress triggered IL6 (147620) production in an NOD1/NOD2-dependent manner. Infection of mice with Brucella abortus, which induces ER stress in a TLR-independent manner, triggered inflammation and Il6 production in a Traf2 (601895)-, Nod1/Nod2-, and Rip2-dependent manner. B. abortus-induced inflammation and Il6 production could be reduced by treatment with an ER-stress inhibitor or an Ire1a (ERN1; 604033) kinase inhibitor. Keestra-Gounder et al. (2016) concluded that an NOD1/NOD2-dependent pathway mediates ER-stress-induced proinflammatory responses, providing a link between NOD1, NOD2, and inflammatory diseases involving ER stress, such as Crohn disease and type-2 diabetes (NIDDM; 125853). </p><p>The human commensal Bacteroides fragilis delivers immunomodulatory molecules to immune cells via secretion of outer membrane vesicles (OMVs). Chu et al. (2016) found that OMVs require the inflammatory bowel disease (IBD; see 266600)-associated genes ATG16L1 and NOD2 to activate a noncanonical autophagy pathway during protection from colitis. ATG16L1-deficient dendritic cells do not induce regulatory T cells (T(regs)) to suppress mucosal inflammation. Immune cells from human subjects with a major risk variant in ATG16L1 are defective in T(reg) responses to OMVs. Chu et al. (2016) proposed that polymorphisms in susceptibility genes promote disease through defects in 'sensing' protective signals from the microbiome, defining a potentially critical gene-environment etiology for IBD. </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><strong><em>Susceptibility to Inflammatory Bowel Disease</em></strong></p><p>
|
|
Ogura et al. (2001) and Hugot et al. (2001) identified mutations in the NOD2 gene (see, e.g., 605956.0001-605956.0003) that were associated with susceptibility to Crohn disease (IBD1; 266600). </p><p>Murillo et al. (2002) studied 130 Dutch patients with Crohn disease, with a median follow-up of 9.2 years, and 152 ethnically matched healthy controls. They confirmed reports that the CARD15 3020insC mutation (605956.0001) increases susceptibility to Crohn disease, but could not confirm the relationship for the CARD15 low frequency G908R missense mutation (605956.0002) reported by Ogura et al. (2001). </p><p>Lesage et al. (2002) reported mutation analysis of the CARD15 gene in 453 patients with Crohn disease, including 166 sporadic and 287 familial cases, 159 patients with ulcerative colitis (IBD1; 266600), and 103 healthy control subjects. Although no mutations were found to be associated with ulcerative colitis, 50% of patients with Crohn disease carried at least 1 potential disease-causing mutation, including 17% who had a double mutation. There were 27 rare additional mutations. Each of 3 polymorphisms (R702W, 605956.0003; G908R, 605956.0002; and 1007fs, 605956.0001) were confirmed to be intermittently associated with susceptibility to Crohn disease. These 3 main variants represented 32%, 18%, and 31%, respectively, of the total Crohn disease mutations, whereas the total of the 27 rare mutations represented 19% of disease-causing mutations. Altogether, 93% of the mutations were located in the distal third of the gene. These observations confirmed the gene-dosage effect in Crohn disease. Patients with double-dose mutations were characterized by a younger age at onset, a more frequent stricturing phenotype, and a less frequent colonic involvement than were seen in those patients who had no mutation. The severity of the disease and extraintestinal manifestations were not different for any of the CARD15 genotypes. The proportion of familial and sporadic cases and the proportion of patients with smoking habits were similar in the groups of Crohn disease patients with or without mutation. </p><p>Among 483 Japanese patients with Crohn disease, Yamazaki et al. (2002) tested for the 3 mutations found to be independent risk factors for Crohn disease in Caucasian patients (R702W, G908R, and 1007fs). None of these mutations was identified; only an R702Q substitution was found in a single patient. Direct sequencing of DNA from 96 of these patients in the regions containing the 3 reported major mutations detected no sequence alterations of consequence. Yamazaki et al. (2002) therefore concluded that NOD2/CARD15 is not a major contributor to Crohn disease susceptibility in the Japanese. </p><p>Crohn disease exhibits a 2- to 4-fold increased frequency in Jews as compared with other ethnic/racial groups. Sugimura et al. (2003) sought additional NOD2 mutations in patients with CD, since the 3 coding variants that had been reported were found in only 30 to 40% of patients and could not account for all the linkage between CD and IBD1 locus (266600). They studied 64 Ashkenazi Jewish and 147 non-Jewish white families. After excluding the influence of the 3 independent disease-predisposing mutations (1007fs, G908R, and R702W), significant linkage of the IBD1 locus on chromosome 16 to Crohn disease was found in Jews, with 2 peaks at D16S403 (mean allele sharing (MAS) = 0.70) and D16S411 (MAS = 0.59). They observed an increased frequency of a haplotype carrying only the 268S variant in Jewish patients but not in non-Jews, suggesting the existence of a Jewish-specific additional disease-predisposing factor on this haplotype. Sequencing of this haplotype revealed a new variant: IVS8+158 (referred to as JW1; 605956.0007). The 268S-JW1 combination exhibited a further increased risk (odds ratio = 5.75, p = 0.0005) and the highest population-attributable risk (15.1%) for CD among reported disease-predisposing mutations in Jews. Thus, in Ashkenazi Jews, unrecognized population-specific predisposing factor(s) existed on the 268S-JW1 haplotype at the IBD1 locus. This factor may contribute to the higher risk for CD in Ashkenazi Jews as compared with non-Jews. </p><p>Croucher et al. (2003) examined 23 SNPs in and around the CARD15 gene in large northern European and Korean samples of patients with CD and normal controls. In the European patients, they confirmed that the 3 disease-associated SNPs in CARD15 (R702W, G908R, and 1007fs) occur independently, but noted that they share a common background haplotype, suggesting a common origin and the possibility of an undiscovered, more strongly predisposing mutation. Korean CD patients have a phenotype identical to the European patients, but had not previously been screened for CARD15. The 3 disease-associated SNPs were absent and there was no evidence of association between CARD15 and CD. Croucher et al. (2003) concluded that the disease-associated mutations in Europeans, which are rare, arose after the Asian-European split. </p><p>Van Heel et al. (2003) performed a genomewide scan of 137 Crohn disease affected relative pairs from 112 families. The authors verified linkage of Crohn disease to regions on chromosome 3 (IBD9; 608448; p = 0.0009) and X (p = 0.001) in their cohort. Linkage to chromosome 16 (IBD1; 266600) was observed in Crohn disease pairs not possessing common CARD15 mutations (p = 0.0007), 25 cM q telomeric of CARD15. Evidence for linkage to chromosome 19 (IBD6; 606674) was observed in Crohn disease pairs not possessing CARD15 mutations (p = 0.0001), and in pairs possessing 1 or 2 copies of the IBD5 (606348) risk haplotype (p = 0.0005), with significant evidence for genetic heterogeneity and epistasis, respectively. These analyses demonstrated the complex genetic basis to Crohn disease, and that the discovery of disease-causing variants may be used to aid identification of further susceptibility loci in complex diseases. </p><p>Stoll et al. (2004) identified variants in the DLG5 gene (604090) associated with inflammatory bowel disease. One of the risk-associated DLG5 haplotypes was distinguished from the common haplotype by a nonsynonymous single-nucleotide polymorphism (SNP) 113G-A, resulting in the amino acid substitution arg30-to-gln (R30Q) in the DUF622 domain of DLG5 (604090.0001). The mutation was predicted to impede scaffolding of DLG5. They stratified the study sample according to the presence of risk-associated variants of CARD15 (1007fs, also known as 3020insC, 605956.0001; G908R, 605956.0002; R702W, 605956.0003) to study potential gene-gene interaction. They found a significant difference in association of the 113A variant of DLG5 with Crohn disease in affected individuals carrying the risk-associated CARD15 alleles versus those carrying non-risk-associated CARD15 alleles. This suggested a complex pattern of gene-gene interaction between DLG5 and CARD15, reflecting the complex nature of polygenic diseases. </p><p>In a study of 193 Jewish Israeli CD patients, Karban and Eliakim (2004) failed to replicate the association of the NOD2 IVS+158 variant with Crohn disease, but noted that they found similarity with the results of Sugimura et al. (2003) with regard to the overall risk of carrying 1 of the 3 predisposing CD risk variants (1007fs, G908R, and R702W). </p><p>Li et al. (2004) defined cytokine regulation in mononuclear cells, with muramyl dipeptide (MDP), the minimal NOD2/CARD15 activating component of peptidoglycan. MDP induced a broad array of transcripts, including interleukin-1-beta (IL1B; 147720) and interleukin-8 (IL8; 146930). Leu1007fsinsC homozygotes demonstrated decreased transcriptional response to MDP. Modest induction of IL8 protein was observed in G908R and R702W homozygotes, indicating varying MDP sensitivity of the CD-associated mutations. With MDP plus TNF-alpha (TNFA; 191160), there was a synergistic induction of IL1B secretion. In leu1007fsinsC homozygotes, there was a profound defect in IL1B secretion despite marked induction of IL1B mRNA. Li et al. (2004) concluded that there is posttranscriptional dependency on the CARD15 pathway for IL1B secretion with MDP and TNF-alpha treatment and suggested that a signaling defect of innate immunity to MDP may be an essential underlying defect in the pathogenesis of some CD patients. </p><p>Van Heel et al. (2005) analyzed the cytokine response of peripheral blood mononuclear cells to MDP. MDP induced strong IL8 secretion and substantially upregulated the secretion of TNF-alpha and IL1B induced by Toll-like receptor (see 601194) ligands. At low nanomolar MDP concentrations, these effects were abolished by the most common Crohn disease NOD2/CARD15 double-mutant genotypes (702W/1007fs, 702W/702W, 1007fs/1007fs, and 908R/1007fs). Van Heel et al. (2005) suggested that NOD2 activation provides a priming signal to condition a broad early immune response to pathogens, and that the absence of this priming signal in NOD2-associated CD causes failure of early immune pathogen clearance and explains the abnormal adaptive immune responses to microbial antigens in CD patients. </p><p>Netea et al. (2005) investigated the responses of mononuclear cells from Crohn disease patients to MDP and other muramyl peptides and found that patients homozygous for the NOD2fs mutation were totally unresponsive to a diaminopimelic acid-containing muramyl tripeptide, the specific agonist for NOD1, and to gram-negative bacterial peptidoglycan. In contrast, a Crohn disease patient with the R702W mutation had normal responses to peptidoglycan. RT-PCR analysis indicated that patients with Nod2fs expressed significantly higher levels of peptidoglycan recognition protein S (PGLYRP1; 604963), which may have contributed to the downregulation of NOD1-dependent responses. Netea et al. (2005) concluded that there is unexpected cross-talk between the NOD1 and NOD2 signaling pathways and proposed that NOD1 functional defects may participate in the development of Crohn disease. </p><p>In summarizing previous findings, King et al. (2006) stated that 3 common mutations in the CARD15 gene are associated with susceptibility to CD, and genetic data suggested a gene dosage model with an increased risk of 2- to 4-fold in heterozygotes and 20- to 40-fold in homozygotes. However, the discovery of numerous rare variants of CARD15 indicated that some heterozygotes with the common mutation have a rare mutation on the other CARD15 allele, which would support a recessive model for CD. King et al. (2006) screened CARD15 for mutations in 100 CD patients who were heterozygous for 1 of those 3 common mutations. They developed a strategy for evaluating potential disease susceptibility alleles that involved assessing the degree of evolutionary conservation of involved residues, predicted effects on protein structure and function, and genotyping in a large sample of cases and controls. The evolutionary analysis was aided by sequencing the entire coding region of CARD15 in 3 primates (chimp, gibbon, and tamarin) and aligning the human sequence with these and orthologs from other species. They found that 11 of the 100 CD patients screened had a second potential pathogenic mutation within the exonic and periexonic sequences examined. Assuming that there are no additional pathogenic mutations in noncoding regions, the study of King et al. (2006) suggested that most carriers of the common disease susceptibility alleles are true heterozygotes, and supported evidence for a gene dosage model. Four novel nonsynonymous mutations were detected. </p><p>Medici et al. (2006) studied 23 CARD15 SNPs in a Norwegian population of 476 unrelated IBD patients and 236 controls in comparison to a well-studied German population of IBD patients and controls. They found significantly lower frequencies of the predisposing CARD15 SNPs (1007fs, G908R, and R702W) and no significant associations with CD in the Norwegian samples. The population-attributable risk percentage of the 3 CARD15 variants in the Norwegian cohort was one of the lowest reported for a European population (1.88%). Medici et al. (2006) stated that these results are consistent with a low frequency of the CARD15 variants in the northern European countries where the prevalence of IBD is greatest. </p><p>MacArthur et al. (2012) performed a systematic survey of loss-of-function variants in human protein-coding genes from the 1000 Genomes Study and imputed 417 loss-of-function single-nucleotide variants and indels into a total of 13,241 patients representing 7 complex diseases, such as Crohn disease and rheumatory arthritis, along with 2,938 shared controls, who had previously been subjected to genomewide SNP genotyping (45:Wellcome Trust Case Control Consortium, 2007). MacArthur et al. (2012) confirmed a previously known frameshift indel in the NOD2 gene (rs2066847, 605956.0012) associated with Crohn disease with a genomewide-significant imputed P value of 1.78 x 10(-14) (2 orders of magnitude more significant than the best tag SNP). However, no other loss-of-function variants achieved genomewide significance, suggesting that common gene-disrupting variants play a minor role in complex disease predisposition. </p><p>Rivas et al. (2011) used pooled next-generation sequencing to study 56 genes from regions associated with Crohn disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in 9 independent case-control series (16,054 Crohn disease cases, 12,153 ulcerative colitis cases, and 17,575 healthy controls), they identified 4 additional independent risk factors in NOD2: R311W, S431L, R703C, and N852S. N852S occurred only in Ashkenazi Jewish individuals. </p><p><strong><em>Blau Syndrome</em></strong></p><p>
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|
Blau syndrome (186580) is a rare autosomal dominant disorder characterized by early-onset granulomatous arthritis, uveitis, and skin rash with camptodactyly. In affected members of 4 families with Blau syndrome, Miceli-Richard et al. (2001) identified 3 different heterozygous mutations in the CARD15 gene (R334Q, 605956.0004; L469F, 605956.0005; and R334W, 605956.0006). All mutations were located in the region encoding the nucleotide binding domain of CARD15; mutations identified patients with Crohn disease were located in the leucine-rich repeat domain of CARD15. </p><p>In a 27-year-old Japanese man with systemic granulomatous disease, in whom lack of a family history of the disease led to a diagnosis of 'early-onset sarcoidosis' rather than Blau syndrome, Kanazawa et al. (2004) identified 1 of the same CARD15 mutations (R334W; 605956.0006) as detected in Blau syndrome. </p><p>Kanazawa et al. (2005) retrospectively collected Japanese 'early-onset sarcoidosis' cases in search of CARD15 mutations. Among 10 of these patients, including the patient previously studied by Kanazawa et al. (2004), missense mutations were found in 9: 4 were heterozygous for the R334W mutation (605956.0006) that had been reported in patients diagnosed with Blau syndrome; 4 were heterozygous for different novel missense mutations (see, e.g., 605956.0008); and 1 patient had 2 missense mutations (D382E, 605956.0009 and A612T, 605956.0010). (The pathogenicity of the A612T variant was later called into question.) All of these variants of CARD15 showed increased basal NFKB activity. Kanazawa et al. (2005) concluded that most patients given a diagnosis of early-onset sarcoidosis or Blau syndrome share a common genetic etiology of CARD15 mutations that cause constitutive NFKB activation, and noted that this supported the long-standing hypothesis that sporadic cases of early-onset sarcoidosis and familial cases of Blau syndrome represent different types of the same juvenile systemic granulomatosis syndrome. </p><p>Goyal et al. (2007) reported an unusual case of a 12-year-old girl who presented with persistent focal seizures and MRI signal abnormalities. Brain biopsies showed marked dural granulomatous inflammation with focal extension into the brain parenchyma. Studies for systemic sarcoidosis were negative. Treatment with infliximab, a TNF-alpha inhibitor, resulted in clinical improvement. Family history revealed a paternal uncle and grandfather with Crohn disease, and molecular analysis identified 3 missense mutations in the NOD2 gene in the proband. </p><p><strong><em>Susceptibility to Yao Syndrome</em></strong></p><p>
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In 7 unrelated patients with multisystem autoinflammatory disease (YAOS; 617321), Yao et al. (2011) identified heterozygosity for a known intronic variant in the NOD2 gene, IVS8+158 (605956.0007). Four of the patients also carried the R702W mutation (605956.0003) in NOD2. Yao et al. (2011) stated that the clinical relevance of these gene mutations remained to be determined, and that this disease might be genetically complex rather than mendelian. </p><p>In 22 patients with autoinflammatory disease, including the 7 patients previously studied by Yao et al. (2011), Yao et al. (2013) screened the NOD2 gene and found that all carried at least 1 variant: 21 had the IVS8+158 variant, and 8 had the R702W variant. Yao et al. (2013) suggested that the IVS8+158 variant, particularly in conjunction with the R702W variant, may confer a considerably higher risk of NOD2-associated autoinflammatory disease. The authors also stated that this disorder differed markedly from Blau syndrome (186580), since these patients commonly exhibited spongiotic dermatitis rather than the granulomatous dermatitis of Blau syndrome, and none showed the chronic joint deformity (camptodactyly) and uveitis typical of Blau syndrome. </p><p>Yao et al. (2015) genotyped 143 patients with symptoms suggestive of Yao syndrome for NOD2 variants and identified 54 patients who fulfilled criteria for Yao syndrome, including the presence of NOD2 variants. The IVS8+158 variant was detected in 46 of the 54 patients, including 30 who carried only IVS8+158 and 18 who also carried other known variants, including R702W, 1007fs (605956.0001), and G908R (605956.0002). In addition, 9 other rare NOD2 variants were detected in 13 of the patients. Yao et al. (2015) noted that it remained unclear whether these variants were causative or served as markers indirectly associated with the disease. </p><p>Yao and Kontzias (2022) identified mutations in the NOD2 gene in 11 patients with YAOS; 5 patients had a single mutation (3 with IVS8+158), 5 patients had biallelic mutations (all with IVS8+158 on 1 allele), and 1 patient had 3 mutations. The mutations were identified by next-generation sequencing of a panel of genes associated with periodic fever syndromes. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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Karason et al. (2003) performed a genomewide linkage scan in psoriatic arthritis in a group of 178 patients from 39 Icelandic families and found a lod score of 2.17 on 16q (607507). Further analysis, conditional on paternal transmission to affected individuals, resulted in a lod score of 4.19. The peak of this lod score was within 20 Mb of the CARD15 gene. The region overlapping CARD15 had been implicated by a genomewide scan in psoriasis by Nair et al. (1997). The possibility of a common susceptibility gene shared by psoriasis/psoriatic arthritis and Crohn disease was further supported by epidemiologic studies that noted an increased incidence of psoriasis and psoriatic arthritis in subjects with Crohn disease (Lee et al., 1990). </p><p>In Newfoundland, Rahman et al. (2003) screened 187 patients with psoriatic arthritis and 136 healthy controls for the 3 common, independent sequence variants of CARD15: R702W (605956.0003), leu1007fsinsC (605956.0001), and G908R (605956.0002). In total, 53 of 187 (28.3%) probands with psoriatic arthritis had at least 1 variant of the CARD15 gene, compared with 16 of 136 (11.8%) controls; odds ratio = 2.97, p = 0.0005. Allele frequencies of R702W, leu1007fsinsC, and G908R were 10.43%, 3.21%, and 1.61%, respectively, in patients with psoriatic arthritis, compared with 3.31%, 2.57%, and 0.37%, respectively, in the control patients. CARD15 conferred susceptibility to psoriatic arthritis independent of HLA-Cw*0602 (see HLA-C, 142840), which of the HLA types shows the strongest association with psoriasis (Gladman, 2002). Rahman et al. (2003) stated that CARD15 was the first candidate gene identified in psoriatic arthritis that resides outside the major histocompatibility complex. They referred to CARD15 as a pleiotropic autoimmune gene, since it confers susceptibility to Crohn disease, Blau syndrome, and psoriatic arthritis. </p>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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</h4>
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<p>Hampe et al. (2002) investigated the relationship between specific NOD2 genotypes and phenotypic characteristics of patients with Crohn disease. Hypotheses were generated retrospectively from a group of 446 German patients with this disorder. Positive findings (p less than 0.100) were verified in prospectively established cohorts of 106 German and 55 Norwegian patients with Crohn disease. All patients were genotyped for the main coding mutations in NOD2, denoted SNP8 (R702W), SNP12 (G908R), and SNP13 (1007fs). In the retrospective cohort, 6 clinical characteristics showed noteworthy haplotype association: fistulizing, disease of the ileum and left and right colon, stenosis, and resection. In the German prospective cohort, these haplotype associations could be replicated for ileal disease (p = 0.006) and right colonic disease (p less than 0.001). A similar trend was noted in the Norwegian patients. </p><p>Vermeire et al. (2002) collected a cohort of 231 patients with Crohn disease and 71 healthy control individuals from the Canadian province of Quebec to determine the prevalence of 3 sequence variants: leu1007fsinsC (605956.0001), gly908 to arg (G908R; 605956.0002), and arg702 to trp (R702W; 605956.0003). In this cohort, 45.0% of patients with Crohn disease carried at least 1 variant in the CARD15 gene, compared with 9.0% of control individuals. Allele frequencies of R702W, G908R, and leu1007fsinsC were 12.9%, 5.2%, and 10.3% in patients with Crohn disease, compared with 4.2%, 0.7%, and 0.7% in control individuals, respectively. Analysis of the relationship between genotype and phenotype convincingly demonstrated that CARD15 variants are significantly associated with ileal disease involvement, as opposed to strictly colonic disease (P less than 0.001). Moreover, Vermeire et al. (2002) determined the haplotype structure surrounding this disease gene by genotyping 45 SNPs in the 177-kb region that contains the CARD15 gene. The structure helped clarify the history of these causal mutations. Their analysis showed that CARD15 involvement with Crohn disease is detectable by use of publicly available SNPs alone. </p><p>Van Heel et al. (2002) discussed difficulties facing microsatellite linkage and linkage disequilibrium mapping methods for identifying disease genes in complex traits. They used 27 microsatellite markers encompassing the IBD1 susceptibility locus in 131 sib pairs affected with Crohn disease and in a simplex family cohort. No evidence of linkage was observed, and microsatellite markers close to NOD2 did not show association. However, significant association was confirmed in 294 Crohn disease trios (2 parents and affected offspring) for the NOD2 variants R702W and leu1007fsinsC. </p><p>Using assays based on NFKB activation, Chamaillard et al. (2003) showed that cytosolic CARD15 efficiently detects bacterial peptidoglycan (PGN), reminiscent of the PGN recognition protein surveillance mechanism in Drosophila. The 3 variants that are associated with Crohn disease and 13 additional variants carried by Crohn disease patients demonstrated impaired PGN-dependent response revealing null, hypomorphic, or dominant-negative properties. Quantitative parametrization of this response, computed from the patients' CARD15 genotypes, was predictive of several variable manifestations of Crohn disease. In contrast, CARD15 alleles associated with Blau syndrome (186580) promoted PGN-independent NFKB activation, an observation that accounts for the minimal microbial input in the etiology of this dominant, monogenic inflammatory disorder affecting solely aseptic sites. </p><p>Fidder et al. (2003) studied the frequency of 2 missense and 1 frameshift variant of CARD15 in Israeli Jewish Crohn disease and ulcerative colitis patients. The 2 missense mutations were R675W (605956.0003) and G881R (605956.0002); the frameshift mutation was 980FS981X (605956.0001). Mutations in CARD15 were observed with significantly greater frequency in Crohn disease patients (46/170, 27%) than in ulcerative colitis patients (7/68, 10%) (p = 0.005). Homozygosity and compound heterozygosity was found only in 7 (4%) patients with Crohn disease as compared to none of the ulcerative colitis patients. Similar rates were observed in Ashkenazi and non-Ashkenazi Jewish patients. Age of onset of disease was lower in Ashkenazi mutation carriers as compared to noncarriers of Ashkenazi origin (18.7 vs 25.8 years, respectively). No other phenotypic characteristics could distinguish mutation carriers from noncarriers. </p><p>To determine whether CARD15 mutations account for the higher prevalence of Crohn disease in Ashkenazi Jews, Tukel et al. (2004) assessed the haplotypes and allele frequencies of the common mutations and variants in 219 members of 50 Ashkenazi Jewish and 53 members of 10 Sephardi/Oriental Jewish multiplex families with CD, in 36 Ashkenazi Jewish patients with sporadic CD, and in 246 Ashkenazi and 82 Sephardi/Oriental Jewish controls. A higher frequency of CARD15 mutations was found in Ashkenazi Jewish patients from multiplex families with CD from central (44%) versus eastern (24%) Europe, especially for the G908R and 1007fs mutations, and in Sephardi/Oriental Jewish patients (34.5%) compared with Ashkenazi (10.1%) or Sephardi/Oriental (5.4%) Jewish controls. </p><p>Giachino et al. (2004) analyzed the 3 recurrent CARD15 variants (R702W, G908R, and 1007fs) in 184 CD and 92 UC Italian patients and in 177 healthy controls. They found significant associations for G908R and L1007fs with CD only. Analysis of mutation-phenotype correlations revealed an increased chance of mutation positivity in patients with strictures (OR, 2.76; 95% CI, 1.2-6.3) and fistulas (OR, 2.59; 95% CI 1.0-6.6), and a weaker association with ileal location of disease (OR, 3.03; 95% CI, 0.9-9.8). Giachino et al. (2004) concluded that the CARD15 genotype can serve as an explanatory variable for predicting the pattern of IBD presentation and progression. </p><p>The Wellcome Trust Case Control Consortium (2007) described a joint genomewide association study using the Affymetrix GeneChip 500K Mapping Array Set, undertaken in the British population, which examined approximately 2,000 individuals for each of 7 major diseases and a shared set of approximately 3,000 controls. This analysis identified 9 associations with Crohn disease including CARD15, which was represented by rs17221417 (p = 9.4 x 10(-12)). </p>
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<h4>
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<span class="mim-font">
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<strong>Evolution</strong>
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</span>
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</h4>
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<p>Analysis of the evolution of CARD15 revealed strong conservation of the encoded protein, with identity to the human sequence ranging from 99.1% in the chimp to 44.5% in fugu (King et al., 2006). </p>
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<h4>
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<strong>Animal Model</strong>
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</h4>
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<p>The mouse Nod2 locus is situated on chromosome 8 and comprises 12 exons, 11 of which encode the Nod2 protein. Ogura et al. (2003) performed sequence analysis of the mouse Nod2 gene from 45 different strains and identified extensive polymorphisms involving all exons of the gene. Studies of the polymorphisms demonstrated a conserved role for Nod2 in the response to bacterial components and suggested that selective evolutionary pressure exerted by pathogens may have contributed to the high level of variability of Nod2 sequences in both humans and mice. </p><p>Pauleau and Murray (2003) generated mice lacking Nod2. Nod2 -/- mice were indistinguishable from wildtype mice and manifested no symptoms or pathology consistent with human Crohn disease. Macrophages of Nod2 -/- mice had nearly normal responses to TLR stimulation and to Ifng (147570) and Il10 (124092), which activate and deactivate macrophages, respectively. However, Nod2 -/- weanling mice better survived a lethal lipopolysaccharide (LPS) challenge than did wildtype weanling mice. </p><p>Kobayashi et al. (2005) generated mice deficient in Nod2 by targeted disruption. Nod2-null mice were outwardly healthy and displayed normal lymphoid and myeloid cellular composition in the thymus and spleen. The mice also displayed no overt symptoms of intestinal inflammation when observed for up to 6 months. Kobayashi et al. (2005) showed that protective immunity mediated by Nod2 recognition of bacterial muramyl dipeptide is abolished in Nod2-deficient mice. The mice were susceptible to bacterial infection through oral delivery but not through intravenous or peritoneal delivery. Nod2 is required for the expression of a subgroup of intestinal antimicrobial peptides known as cryptdins. Kobayashi et al. (2005) concluded that the NOD2 protein is a critical mediator of bacterial immunity within the intestine, providing a possible mechanism for NOD2 mutations in Crohn disease. </p><p>Watanabe et al. (2004) studied Nod2 -/- mice and determined that intact Nod2 signaling inhibits Tlr2 (603028)-driven activation of Nfkb (see 164011), particularly its Rel subunit (164910). Nod2 deficiency or the presence of a Crohn disease-like Nod2 mutation increased Tlr2-mediated activation of Nfkb-Rel in association with enhanced Th1 responses. Watanabe et al. (2004) concluded that NOD2 signaling normally inhibits TLR2-driven Th1 responses by regulating NFKB signaling. </p><p>Maeda et al. (2005) generated mice whose Nod2 locus harbors the homolog of the most common Crohn disease susceptibility allele, 3020insC (605956.0001), which encodes a truncated protein lacking the last 33 amino acids. Homozygous Nod2 mutant mice were obtained at the expected mendelian ratio, were healthy, and showed no abnormalities of the gastrointestinal tract or other organs. The mutation had no effect on Nod2 mRNA or protein amounts in bone marrow-derived macrophages. Mutant mice exhibited elevated NFKB activation in response to bacteria-derived muramyl dipeptide and more efficient processing and secretion of the cytokine interleukin-1-beta (IL1B; 147720). These effects were linked to increased susceptibility to bacteria-induced intestinal inflammation and identified NOD2 as a positive regulator of NFKB activation and IL1B secretion. </p><p>By histopathologic analysis, Divangahi et al. (2008) showed that Nod2-deficient mice had reduced inflammatory responses but similar bacterial counts compared with wildtype mice in the first 2 months after infection with Mycobacterium tuberculosis. Nod2-deficient mice infected with the M. bovis BCG vaccine had decreased production of Tnf, Ifng, and Il12p40 (IL12B; 161561) and reduced recruitment of Cd4 (186940)-positive and Cd8 (see 186910)-positive T cells. After 6 months, the bacterial burden was increased in the Nod2-deficient mice and their survival was significantly reduced. Divangahi et al. (2008) concluded that NOD2 mediates resistance to mycobacterial infection via both innate and adaptive immunity. </p><p>Hruz et al. (2009) found that Nod2-deficient mice exhibited a delayed but ultimately exacerbated response to subcutaneous Staphylococcus aureus infection. Nod2 action was dependent on Il1b-amplified production of Il6 (147620), which promoted rapid bacterial killing by neutrophils. Hruz et al. (2009) concluded that NOD2 is not only involved in recognition of organisms in cytoplasm, but that it also contributes to recognition of pathogenic bacteria in the extracellular compartment that elaborate pore-forming toxins. </p><p>T helper-17 (Th17) cells are a subset of CD4-positive helper T cells characterized by secretion of IL17 (603149) and IL22 (605330). Geddes et al. (2011) infected mice with Citrobacter rodentium or Salmonella typhimurium species and observed triggering of early Il17 production that was crucial for host defense mediated by Cd4-positive helper T cells. Th17 responses occurred principally in the cecum and were mediated by innate Th17 cells that were regulated by Nod1 and Nod2. Mice lacking both Nod1 and Nod2 were unable to induce early Th17 responses due to insufficient Il6 production. Geddes et al. (2011) concluded that the NOD-innate Th17 axis, which is dependent on IL6 expression and requires intestinal microbiota for induction, is a key element of mucosal immunity against bacterial pathogens. </p>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>12 Selected Examples):</strong>
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</span>
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</h4>
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<p />
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<h4>
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<span class="mim-font">
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<strong>.0001 INFLAMMATORY BOWEL DISEASE 1 (CROHN DISEASE), SUSCEPTIBILITY TO</strong>
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</h4>
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<span class="mim-text-font">
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YAO SYNDROME, SUSCEPTIBILITY TO, INCLUDED
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</span>
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NOD2, 1-BP INS, 3020C
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<br />
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SNP: rs2066847,
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gnomAD: rs2066847,
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ClinVar: RCV000334899, RCV000389442, RCV000416485, RCV001529584, RCV001701717, RCV001781184, RCV002260960, RCV002468553, RCV002512781, RCV003224089
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<span class="mim-text-font">
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<p />
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<p><strong><em>Inflammatory Bowel Disease 1 (Crohn Disease), Susceptibility to</em></strong></p><p>
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Ogura et al. (2001) sequenced all coding exons and flanking introns of the NOD2 gene in 12 affected individuals from pure Crohn disease (IBD1; 266600) families with increased linkage scores at D16S3396, which is tightly linked to NOD2, as well as in 4 case controls. In 3 Crohn disease patients, they identified a 1-bp insertion (C) at nucleotide 3020 (3020insC) in exon 11 of the NOD2 gene, resulting in a frameshift at the second nucleotide of codon 1007 (1007fs) and a leu1007-to-pro substitution in the tenth LRR, followed by a premature stop codon. The predicted truncated NOD2 protein contained 1,007 amino acids instead of the 1,040 amino acids of the wildtype protein. Ogura et al. (2001) observed preferential transmission from heterozygous parents to affected children of the 3020insC mutation (P of 0.0046). There was no preferential transmission of this mutation in families with ulcerative colitis. The frequency of the 3020insC mutation was 8.4% among Jewish Caucasians and 8.1% among non-Jewish Caucasians. The frequency among control Caucasians was 4.0%. The allele frequency of this mutation from 182 unrelated ulcerative colitis patients was 3.0%. The genotype frequencies of the 3020insC mutation in unrelated Crohn disease individuals was 11 homozygotes, 46 heterozygotes, and 359 wildtype homozygotes. The genotype-relative risk for heterozygous and homozygous 3020insC was 1.5 and 17.6, respectively, as compared with wildtype controls. Lipopolysaccharide (LPS) from various bacteria induced nuclear factor kappa-B (NFKB; see 164011) activation in cells expressing wildtype NOD2, but not in cells transfected with control plasmid. Cells transfected with NOD2 carrying the 3020insC mutation had greatly diminished response to LPS, with the most significant reduction in response to Salmonella, Shigella, Klebsiella, Campylobacter, and Neisseria gonorrhoeae. </p><p>Hugot et al. (2001) independently identified this mutation in association with Crohn disease; however, because they used the 1,013-amino acid NOD2B sequence, they reported the mutation as a frameshift at codon 980. </p><p>Hampe et al. (2001) studied the association between this mutation and inflammatory bowel disease in 512 affected individuals from 309 German or British families, 369 German trios (patients with sporadic inflammatory bowel disease and their unaffected parents), and 272 normal controls. Family-based association analyses were consistently positive in 95 British and 99 German affected sib pairs with Crohn disease; the association was confirmed in 304 German trios with Crohn disease. No association was seen in the 115 sib pairs and 65 trios with ulcerative colitis. The genotype-specific disease risks conferred by heterozygous and homozygous mutant genotypes were 2.6 and 42.1, respectively. </p><p>A genetically impaired intestinal barrier function has long been suspected to be a predisposing factor for Crohn disease. To test the association of CARD15 with intestinal permeability, Buhner et al. (2006) studied 128 patients with quiescent CD, 129 first-degree relatives, 66 nonrelated household members, and 96 healthy controls. There were 3 main findings. Healthy first-degree relatives of patients with CD showed increased permeability in contrast with unrelated household members and controls. Secondly, the prevalence of the CARD15 3020insC mutation was similar in first-degree relatives and CD patients and higher compared with controls. Thirdly, in healthy first-degree relatives, high mucosal permeability and the presence of a CARD15 3020insC mutation were significantly associated. </p><p><strong><em>Yao Syndrome, Susceptibility to</em></strong></p><p>
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Among 54 patients with multisystem inflammatory disease and variants in the NOD2 gene, or Yao syndrome (YAOS; 617321), Yao et al. (2015) identified 2 patients who were compound heterozygous for the IVS8+158 variant (605956.0007) and the 1007fs mutation in NOD2. The authors noted that it remained unclear whether these variants were causative or served as markers indirectly associated with the disease. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 INFLAMMATORY BOWEL DISEASE 1 (CROHN DISEASE), SUSCEPTIBILITY TO</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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YAO SYNDROME, SUSCEPTIBILITY TO, INCLUDED
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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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NOD2, GLY908ARG
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<br />
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SNP: rs2066845,
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gnomAD: rs2066845,
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ClinVar: RCV000238745, RCV000268347, RCV000416490, RCV000996266, RCV001781185, RCV002054415, RCV002260961, RCV002512782
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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 />
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<p><strong><em>Inflammatory Bowel Disease 1 (Crohn Disease), Susceptibility to</em></strong></p><p>
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Hugot et al. (2001) identified a mutation leading to a gly881-to-arg (GLY881ARG) substitution in the NOD2 gene that was associated with an increased susceptibility to Crohn disease (IBD1; 266600). The allele frequency of this mutation was 0.11 among Crohn disease patients, 0.03 among ulcerative colitis (IBD1; 266600) patients, and 0.04 among unaffected controls. </p><p>This mutation was designated GLY908ARG in the studies of Ogura et al. (2001) and Vermeire et al. (2002). </p><p><strong><em>Yao Syndrome, Susceptibility to</em></strong></p><p>
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Among 54 patients with multisystem inflammatory disease and variants in the NOD2 gene, or Yao syndrome (YAOS; 617321), Yao et al. (2015) identified 1 patient who carried 3 NOD2 variants: G908R, R702W (605956.0003), and IVS8+158 (605956.0007). The authors noted that it remained unclear whether these variants were causative or served as markers indirectly associated with the disease. </p>
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</span>
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</div>
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<div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 INFLAMMATORY BOWEL DISEASE 1 (CROHN DISEASE), SUSCEPTIBILITY TO</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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YAO SYNDROME, SUSCEPTIBILITY TO, INCLUDED
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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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NOD2, ARG702TRP
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<br />
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SNP: rs2066844,
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gnomAD: rs2066844,
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ClinVar: RCV000203217, RCV000365422, RCV000416493, RCV001535441, RCV001781186, RCV001810832, RCV002262557, RCV002512783
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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 />
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<p><strong><em>Inflammatory Bowel Disease 1 (Crohn Disease), Susceptibility to</em></strong></p><p>
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Hugot et al. (2001) identified a mutation leading to an arg675-to-trp (ARG675TRP) substitution in the NOD2 gene that was associated with increased susceptibility to Crohn disease (IBD1; 266600). The allele frequency of this mutation was 0.06 among Crohn disease patients, 0.01 among unaffected controls, and it was not present among ulcerative colitis patients. </p><p>This mutation was designated ARG702TRP in the study of Vermeire et al. (2002). </p><p><strong><em>Yao Syndrome, Susceptibility to</em></strong></p><p>
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In 4 unrelated patients with multisystem autoinflammatory disease (YAOS; 617321), Yao et al. (2011) identified heterozygosity for the R702W mutation in the NOD2 gene. The patients also carried the known intronic variant IVS8+158 in NOD2 (605956.0007). Yao et al. (2011) stated that the clinical relevance of these mutations remained to be determined, and that this disease might be genetically complex rather than mendelian. </p><p>In a cohort of 22 patients with autoinflammatory disease that included the 7 patients previously studied by Yao et al. (2011), Yao et al. (2013) screened the NOD2 gene and identified heterozygosity for the R702W variant in 8 patients, all but 1 of whom also carried the IVS8+158 variant. Five of the 8 patients had varying degrees of gastrointestinal symptoms, but Yao et al. (2013) found no evidence of Crohn disease or ulcerative colitis after extensive evaluation. </p><p>Among 54 patients with multisystem inflammatory disease and variants in the NOD2 gene, Yao et al. (2015) identified 14 patients who were compound heterozygous for IVS8+158 and the R702W variant. The authors noted that it remained unclear whether these variants were causative or served as markers indirectly associated with the disease. </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 BLAU SYNDROME</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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NOD2, ARG334GLN
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<br />
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SNP: rs104895461,
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ClinVar: RCV000004958, RCV000482720, RCV002512784
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of 2 families with Blau syndrome (BLAUS; 186580), Miceli-Richard et al. (2001) found a 1001G-A transition in the NOD2 gene, resulting in an arg334-to-gln (R334Q) amino acid change. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 BLAU SYNDROME</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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NOD2, LEU469PHE
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<br />
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SNP: rs104895460,
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ClinVar: RCV000004959
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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 proband and his father with Blau syndrome (BLAUS; 186580), Miceli-Richard et al. (2001) found a 1405C-T transition in the NOD2 gene, resulting in a leu469-to-phe (L469F) amino acid change. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 BLAU SYNDROME</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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NOD2, ARG334TRP
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<br />
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SNP: rs104895462,
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ClinVar: RCV000004960, RCV001509512, RCV002512785
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In affected members of a family with Blau syndrome (BLAUS; 186580), Miceli-Richard et al. (2001) found a 1000C-T transition in the NOD2 gene, resulting in an arg334-to-trp (R334W) substitution. </p><p>In a 27-year-old Japanese man who had dermatitis and arthritis in infancy and later developed severe eye inflammation, persistent low-grade fever, and camptodactyly, Kanazawa et al. (2004) identified heterozygosity for the R334W mutation in the NOD2 gene. </p><p>In 4 Japanese patients with early-onset sarcoidosis (Blau syndrome), including a patient originally reported by Sakurai et al. (1997) and the 27-year-old man previously studied by Kanazawa et al. (2004), Kanazawa et al. (2005) identified heterozygosity for the R334W mutation in the NOD2 gene. </p><p>In a 63-year-old man with Blau syndrome, who exhibited severe camptodactyly and bilateral leg ulcerations, Dhondt et al. (2008) identified heterozygosity for the R334W mutation in the central nucleotide-binding oligomerization domain. </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>
|
|
<span class="mim-font">
|
|
<strong>.0007 INFLAMMATORY BOWEL DISEASE 1 (CROHN DISEASE), SUSCEPTIBILITY TO</strong>
|
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</span>
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
|
|
BLAU SYNDROME, INCLUDED<br />
|
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YAO SYNDROME, SUSCEPTIBILITY TO, INCLUDED
|
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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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NOD2, IVS8+158
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<br />
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SNP: rs5743289,
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gnomAD: rs5743289,
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ClinVar: RCV000416486, RCV000416489, RCV000960463, RCV001029749, RCV001781187, RCV005208820
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
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<p />
|
|
<p><strong><em>Inflammatory Bowel Disease 1 (Crohn Disease), Susceptibility to</em></strong></p><p>
|
|
In 112 Ashkenazi Jewish patients with Crohn disease (IBD1; 266600), Sugimura et al. (2003) found a novel disease-predisposing variant in the NOD2 gene, IVS8+158, which is a C-to-T mutation in the palindrome sequence in the intron 8 splicing region. The IVS8+158 variant, which the authors designated 'JW1,' occurred on a specific haplotype with a 268S variant, and this combination exhibited a further increased risk (odds ratio = 5.75, p = 0.0005) and the highest population-attributable risk (15.1%) for Crohn disease (CD) among reported disease-predisposing mutations in Jews. However, no association was found between the 268S-JW1 haplotype and disease in 166 non-Jewish white CD patients. Sugimura et al. (2003) concluded that in Ashkenazi Jews, unrecognized population-specific predisposing factor(s) for CD exist on the 268S-JW1 haplotype at the IBD1 locus. </p><p>In a study of 193 Jewish Israeli CD patients, Karban and Eliakim (2004) failed to replicate the association of the S268P variant or S268P-IVS+158 combination with Crohn disease. </p><p>Tukel et al. (2004) assessed the haplotypes and allele frequencies of the common NOD2 mutations and variants in 219 members of 50 Ashkenazi Jewish and 53 members of 10 Sephardi/Oriental Jewish multiplex families with CD, in 36 Ashkenazi Jewish patients with sporadic CD, and in 246 Ashkenazi and 82 Sephardi/Oriental Jewish controls, and found no evidence for increased risk associated with the IVS8+158 variant. </p><p><strong><em>Blau Syndrome</em></strong></p><p>
|
|
In a 9-month-old Caucasian boy with Blau syndrome (BLAUS; 186580), Borzutzky et al. (2010) identified heterozygosity for the IVS8+158 variant in the NOD2 gene. Borzutzky et al. (2010) stated that this was the first reported case of gastrointestinal granulomas in a patient with early-onset sarcoidosis. </p><p><strong><em>Yao Syndrome, Susceptibility to</em></strong></p><p>
|
|
In 7 unrelated patients with multisystem autoinflammatory disease (YAOS; 617321), Yao et al. (2011) identified heterozygosity for the IVS8+158 variant in the NOD2 gene. Four of the patients also carried the R702W mutation in NOD2 (605956.0003). Yao et al. (2011) stated that the clinical relevance of these gene mutations remained to be determined, and that this disease might be genetically complex rather than mendelian. </p><p>In 22 patients with autoinflammatory disease, including the 7 patients previously studied by Yao et al. (2011), Yao et al. (2013) screened the NOD2 gene and found that all carried at least 1 variant: 21 had the IVS8+158 variant, and 8 had the R702W variant. Yao et al. (2013) noted that the allele frequency of the IVS8+158 variant in the healthy white population had been estimated to be approximately 15% by Sugimura et al. (2003), whereas in an aggregated cohort of 41 patients tested by Yao et al. (2013) for IVS8+158, the variant was detected in approximately 55% of patients (p less than 0.001), all of whom were non-Jewish. </p><p>Yao et al. (2015) genotyped 143 patients with symptoms suggestive of Yao syndrome for NOD2 variants and identified 54 patients who fulfilled criteria for the disorder, including the presence of NOD2 variants. The IVS8+158 variant was detected in 46 of the 54 patients, including 30 who carried only IVS8+158 and 18 who also carried other known variants, including R702W, 3020insC (605956.0001), and G908R (605956.0002). In addition, 9 other rare NOD2 variants were detected in 13 of the patients. Yao et al. (2015) noted that it remained unclear whether these variants were causative or served as markers indirectly associated with the disease. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
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<div>
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 BLAU SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
NOD2, HIS496LEU
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|
|
<br />
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|
|
SNP: rs104895472,
|
|
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|
|
|
|
|
ClinVar: RCV000416481
|
|
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|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 32-year-old woman with Blau syndrome (BLAUS; 186580), originally described by Shimomura et al. (1982) as a case of 'ocular sarcoidosis,' Kanazawa et al. (2005) identified heterozygosity for a 1487A-T transversion in the NOD2 gene, resulting in a his496-to-leu (H496L) substitution. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 BLAU SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
NOD2, ASP382GLU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104895476,
|
|
|
|
|
|
gnomAD: rs104895476,
|
|
|
|
|
|
ClinVar: RCV000416482, RCV003764528
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 16-year-old girl with Blau syndrome (BLAUS; 186580), originally reported by Ukae et al. (1994) as a case of 'preschool sarcoidosis,' Kanazawa et al. (2005) identified 2 missense mutations in the CARD15 gene: a 1146C-G transversion, resulting in an asp382-to-glu (D382E) substitution, and a 1834G-A transition, resulting in an ala612-to-thr (A612T) substitution (605956.0010). Kanazawa et al. (2005) noted that the A612T mutation, which previously had been detected in a patient with Crohn disease (IBD1; 266600) by Lesage et al. (2002), was also found in heterozygosity in 1 of 100 Japanese controls. Hamosh (2017) noted that the allelic frequency of the A612T mutation in the ExAC database (February 22, 2017) suggests that this variant is not pathogenic. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
NOD2, ALA612THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104895438,
|
|
|
|
|
|
gnomAD: rs104895438,
|
|
|
|
|
|
ClinVar: RCV000328692, RCV001280996, RCV001781188, RCV002512787, RCV003421904
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant, previously designated BLAU SYNDROME, has been reclassified based on a review of the ExAC database by Hamosh (2017).</p><p>Kanazawa et al. (2005) reported an ala612-to-thr (A612T) substitution in the CARD15 gene in compound heterozygous state with an asp382-to-glu (D382E; 605956.0009) substitution in a patient with Blau syndrome (BLAUS; 186580). They noted that the A612T mutation was also found in heterozygosity in 1 of 100 Japanese controls. </p><p>Hamosh (2017) found the A nucleotide (resulting in thr at residue 612) in 77 of 121,180 alleles and in homozygosity in 1 individual in the ExAC database (February 22, 2017), suggesting that the variant is not pathogenic.</p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
|
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 BLAU SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
NOD2, GLU383LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104895477,
|
|
|
|
|
|
gnomAD: rs104895477,
|
|
|
|
|
|
ClinVar: RCV000004966, RCV002512788
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a mother and daughter with Blau syndrome (BLAUS; 186580), van Duist et al. (2005) identified a heterozygous 1147G-A transition in exon 4 of the CARD15 gene, resulting in a glu383-to-lys (E383K) substitution. The mutation is in a highly conserved region in the central nucleotide-binding NACHT domain and may result in increased signaling. </p>
|
|
</span>
|
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</div>
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<div>
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<br />
|
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</div>
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</div>
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<div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 INFLAMMATORY BOWEL DISEASE 1 (CROHN DISEASE), SUSCEPTIBILITY TO</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
NOD2, 1-BP INS, 3016C ({dbSNP rs2066847})
|
|
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|
|
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<br />
|
|
|
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|
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|
|
ClinVar: RCV000334899, RCV000389442, RCV000416485, RCV001529584, RCV001701717, RCV001781184, RCV002260960, RCV002468553, RCV002512781, RCV003224089
|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>MacArthur et al. (2012) reported a 1-bp insertion (3016_3017insC) in the NOD2 gene, leading to a frameshift, that was associated with Crohn disease (IBD1; 266600). The genomewide-significant imputed P value was 1.78 x 10(-14), just 2 orders of magnitude more significant than the best tag SNP. </p>
|
|
</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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<div>
|
|
<ol>
|
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<li>
|
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<p class="mim-text-font">
|
|
Borzutzky, A., Fried, A., Chou, J., Bonilla, F. A., Kim, S., Dedeoglu, F.
|
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<strong>NOD2-associated diseases: bridging innate immunity and autoinflammation.</strong>
|
|
Clin. Immun. 134: 251-261, 2010.
|
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[PubMed: 19467619]
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[Full Text: https://doi.org/10.1016/j.clim.2009.05.005]
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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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Brain, O., Owens, B. M. J., Pichulik, T., Allan, P., Khatamzas, E., Leslie, A., Steevels, T., Sharma, S., Mayer, A., Catuneanu, A. M., Morton, V., Sun, M.-Y., Jewell, D., Coccia, M., Harrison, O., Maloy, K., Schonefeldt, S., Bornschein, S., Liston, A., Simmons, A.
|
|
<strong>The intracellular sensor NOD2 induces microRNA-29 expression in human dendritic cells to limit IL-23 release.</strong>
|
|
Immunity 39: 521-536, 2013.
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[PubMed: 24054330]
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[Full Text: https://doi.org/10.1016/j.immuni.2013.08.035]
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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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Buhner, S., Buning, C., Genschel, J., Kling, K., Herrmann, D., Dignass, A., Kuechler, I., Krueger, S., Schmidt, H. H.-J., Lochs, H.
|
|
<strong>Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation?</strong>
|
|
Gut 55: 342-347, 2006.
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[PubMed: 16000642]
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[Full Text: https://doi.org/10.1136/gut.2005.065557]
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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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Chamaillard, M., Philpott, D., Girardin, S. E., Zouali, H., Lesage, S., Chareyre, F., Bui, T. H., Giovannini, M., Zaehringer, U., Penard-Lacronique, V., Sansonetti, P. J., Hugot, J.-P., Thomas, G.
|
|
<strong>Gene-environment interaction modulated by allelic heterogeneity in inflammatory diseases.</strong>
|
|
Proc. Nat. Acad. Sci. 100: 3455-3460, 2003.
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[PubMed: 12626759]
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[Full Text: https://doi.org/10.1073/pnas.0530276100]
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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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Chu, H., Khosravi, A., Kusumawardhani, I. P., Kwon, A. H. K., Vasconcelos, A. C., Cunha, L. D., Mayer, A. E., Shen, Y., Wu, W.-L., Kambal, A., Targan, S. R., Xavier, R. J., Ernst, P. B., Green, D. R., McGovern, D. P. B., Virgin, H. W., Mazmanian, S. K.
|
|
<strong>Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease.</strong>
|
|
Science 352: 1116-1120, 2016.
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 06/27/2023<br>Ada Hamosh - updated : 02/22/2017<br>Marla J. F. O'Neill - updated : 01/31/2017<br>Ada Hamosh - updated : 09/01/2016<br>Matthew B. Gross - updated : 08/11/2016<br>Paul J. Converse - updated : 08/11/2016<br>Paul J. Converse - updated : 9/22/2014<br>Ada Hamosh - updated : 6/2/2014<br>Ada Hamosh - updated : 7/23/2012<br>Ada Hamosh - updated : 2/27/2012<br>Paul J. Converse - updated : 8/5/2011<br>Paul J. Converse - updated : 9/28/2010<br>Paul J. Converse - updated : 2/4/2010<br>Paul J. Converse - updated : 1/7/2010<br>Cassandra L. Kniffin - updated : 6/2/2009<br>Cassandra L. Kniffin - updated : 11/30/2007<br>Patricia A. Hartz - updated : 10/31/2007<br>Ada Hamosh - updated : 7/24/2007<br>Victor A. McKusick - updated : 5/31/2007<br>George E. Tiller - updated : 1/16/2007<br>Marla J. F. O'Neill - updated : 5/24/2006<br>Victor A. McKusick - updated : 1/20/2006<br>Paul J. Converse - updated : 10/27/2005<br>Marla J. F. O'Neill - updated : 9/1/2005<br>Cassandra L. Kniffin - updated : 7/11/2005<br>Victor A. McKusick - updated : 3/21/2005<br>Victor A. McKusick - updated : 3/15/2005<br>Ada Hamosh - updated : 2/25/2005<br>Marla J. F. O'Neill - updated : 5/3/2004<br>George E. Tiller - updated : 4/28/2004<br>Victor A. McKusick - updated : 4/27/2004<br>Victor A. McKusick - updated : 4/21/2004<br>Marla J. F. O'Neill - updated : 4/2/2004<br>Victor A. McKusick - updated : 10/8/2003<br>Victor A. McKusick - updated : 9/5/2003<br>Victor A. McKusick - updated : 5/2/2003<br>Victor A. McKusick - updated : 4/25/2003<br>Victor A. McKusick - updated : 3/3/2003<br>Victor A. McKusick - updated : 2/26/2003<br>Victor A. McKusick - updated : 10/1/2002<br>Victor A. McKusick - updated : 9/24/2002<br>Victor A. McKusick - updated : 9/12/2002<br>Victor A. McKusick - updated : 7/17/2002<br>Victor A. McKusick - updated : 6/26/2002<br>Victor A. McKusick - updated : 4/12/2002<br>Victor A. McKusick - updated : 3/1/2002<br>Victor A. McKusick - updated : 8/23/2001<br>Ada Hamosh - updated : 5/22/2001
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Creation Date:
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Paul J. Converse : 5/22/2001
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