5258 lines
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Entry
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- *606951 - INTERFERON-INDUCED HELICASE C DOMAIN-CONTAINING PROTEIN 1; IFIH1
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- OMIM
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<p>
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<span class="h4">*606951</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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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/606951">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000115267;t=ENST00000649979" 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=64135" 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=606951" 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=ENSG00000115267;t=ENST00000649979" 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_022168,XM_047445407" 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_022168" 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=606951" 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=09507&isoform_id=09507_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/IFIH1" 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/11344594,12621066,16551654,27886568,28279331,50415795,62702211,62988819,84627487,119631757,134047802,158259343,2217330120,2462575953" 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/Q9BYX4" 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=64135" 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=ENSG00000115267;t=ENST00000649979" 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=IFIH1" 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=IFIH1" 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+64135" 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/IFIH1" 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:64135" 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/64135" 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=chr2&hgg_gene=ENST00000649979.2&hgg_start=162267074&hgg_end=162318684&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:18873" 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/ifih1" 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=606951[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=606951[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/IFIH1/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/ENSG00000115267" 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=IFIH1" 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=IFIH1" 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=IFIH1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=IFIH1&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/PA134889215" 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:18873" 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:1918836" 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/IFIH1#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:1918836" 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/64135/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=64135" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00001090;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-081104-438" 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">
|
|
<div style="display: table-row">
|
|
<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
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|
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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:64135" 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=IFIH1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
|
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
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606951
|
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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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INTERFERON-INDUCED HELICASE C DOMAIN-CONTAINING PROTEIN 1; IFIH1
|
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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">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
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</p>
|
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</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
MELANOMA DIFFERENTIATION-ASSOCIATED GENE 5; MDA5
|
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</span>
|
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</h4>
|
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</div>
|
|
</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=IFIH1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">IFIH1</a></em></strong>
|
|
</span>
|
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</p>
|
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</div>
|
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/2/727?start=-3&limit=10&highlight=727">2q24.2</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr2:162267074-162318684&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'})">2:162,267,074-162,318,684</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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|
|
|
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|
|
</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=615846,619773,182250" 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/2/727?start=-3&limit=10&highlight=727">
|
|
2q24.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Aicardi-Goutieres syndrome 7
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/615846"> 615846 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
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|
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</tr>
|
|
|
|
|
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|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Immunodeficiency 95
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/619773"> 619773 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Singleton-Merten syndrome 1
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/182250"> 182250 </a>
|
|
|
|
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<p>The IFIH1 gene encodes a cytoplasmic receptor that senses dsRNA viral products to activate type I interferon signaling through the MAVS (<a href="/entry/609676">609676</a>) adaptor molecule. This can inhibit virus replication and modulate cellular immune responses. IFIH1 may also help recognize and limit the replication of ssRNA viruses (summary by <a href="#20" class="mim-tip-reference" title="Rice, G. I., del Toro Duany, Y., Jenkinson, E. M., Forte, G. M. A., Anderson, B. H., Ariaudo, G., Bader-Meunier, B., Baildam, E. M., Battini, R., Beresford, M. W., Casarano, M., Chouchane, M., and 41 others. <strong>Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling.</strong> Nature Genet. 46: 503-509, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24686847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24686847</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24686847[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.2933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24686847">Rice et al., 2014</a> and <a href="#16" class="mim-tip-reference" title="Lamborn, I. T., Jing, H., Zhang, Y., Drutman, S. B., Abbott, J. K., Munir, S., Bade, S., Murdock, H. M., Santos, C. P., Brock, L. G., Masutani, E., Fordjour, E. Y., and 14 others. <strong>Recurrent rhinovirus infections in a child with inherited MDA5 deficiency.</strong> J. Exp. Med. 214: 1949-1972, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28606988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28606988</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28606988[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20161759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28606988">Lamborn et al., 2017</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=28606988+24686847" 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 screening a melanoma differentiation-subtracted library and a placenta cDNA library, followed by 5-prime RACE, <a href="#14" class="mim-tip-reference" title="Kang, D., Gopalkrishnan, R. V., Wu, Q., Jankowsky, E., Pyle, A. M., Fisher, P. B. <strong>mda-5: an interferon-inducible putative RNA helicase with double-stranded RNA-dependent ATPase activity and melanoma growth-suppressive properties.</strong> Proc. Nat. Acad. Sci. 99: 637-642, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11805321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11805321</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11805321[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.022637199" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11805321">Kang et al. (2002)</a> isolated a full-length cDNA encoding IFIH1, which they called MDA5. The deduced 1,025-amino acid protein contains an N-terminal CARD motif and a C-terminal DExH/D RNA helicase domain closely related to that of RIGI (DDX58; <a href="/entry/609631">609631</a>). SDS-PAGE and Western blot analysis showed expression of a 120-kD protein. Northern blot analysis revealed that treatment of melanoma cells or skin fibroblasts with beta-interferon (IFNB; <a href="/entry/147640">147640</a>) enhanced MDA5 expression 3-fold more than did treatment with IFNA (<a href="/entry/147660">147660</a>), IFNG (<a href="/entry/147570">147570</a>), or tumor necrosis factor (TNF; <a href="/entry/191160">191160</a>). Other differentiation reagents had little or no effect. Expression of MDA5 was further upregulated in the presence of mezerein (MEZ). In tissues, expression of MDA5 was low overall, with highest levels in placenta, pancreas, and spleen, and undetectable levels in brain, lung, and testis. Confocal microscopy demonstrated cytoplasmic expression corresponding with the absence of a nuclear localization signal in the primary amino acid sequence. Ectopic expression of MDA5 in melanoma cells resulted in reduced colony formation, suggesting an interaction of the CARD and apoptotic signal molecules. Functional analysis indicated that MDA5 is an RNA-dependent ATPase. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11805321" 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 fluorescence immunohistochemistry, <a href="#24" class="mim-tip-reference" title="Rutsch, F., MacDougall, M., Lu, C., Buers, I., Mamaeva, O., Nitschke, Y., Rice, G. I., Erlandsen, H., Kehl, H. G., Thiele, H., Nurnberg, P., Hohne, W., Crow, Y. J., Feigenbaum, A., Hennekam, R. C. <strong>A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome.</strong> Am. J. Hum. Genet. 96: 275-282, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25620204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25620204</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25620204[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2014.12.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25620204">Rutsch et al. (2015)</a> detected MDA5 in human cardiac myocytes, epidermis, and cartilage chondrocytes. Analysis of mouse mandibles demonstrated localization of Mda5 in ameloblasts, odontoblasts, and the periodontal ligament, as well as in active osteoblasts at the surface of alveolar bone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25620204" 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="#13" class="mim-tip-reference" title="Kang, D., Gopalkrishnan, R. V., Lin, L., Randolph, A., Valerie, K., Pestka, S., Fisher, P. B. <strong>Expression analysis and genomic characterization of human melanoma differentiation associated gene-5, mda-5: a novel type I interferon-responsive apoptosis-inducing gene.</strong> Oncogene 23: 1789-1800, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14676839/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14676839</a>] [<a href="https://doi.org/10.1038/sj.onc.1207300" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14676839">Kang et al. (2004)</a> determined that the IFIH1 gene contains 16 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14676839" 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 radiation hybrid and genomic sequence analyses, <a href="#13" class="mim-tip-reference" title="Kang, D., Gopalkrishnan, R. V., Lin, L., Randolph, A., Valerie, K., Pestka, S., Fisher, P. B. <strong>Expression analysis and genomic characterization of human melanoma differentiation associated gene-5, mda-5: a novel type I interferon-responsive apoptosis-inducing gene.</strong> Oncogene 23: 1789-1800, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14676839/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14676839</a>] [<a href="https://doi.org/10.1038/sj.onc.1207300" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14676839">Kang et al. (2004)</a> mapped the IFIH1 gene to chromosome 2q24. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14676839" 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>Using Northern blot analysis, <a href="#13" class="mim-tip-reference" title="Kang, D., Gopalkrishnan, R. V., Lin, L., Randolph, A., Valerie, K., Pestka, S., Fisher, P. B. <strong>Expression analysis and genomic characterization of human melanoma differentiation associated gene-5, mda-5: a novel type I interferon-responsive apoptosis-inducing gene.</strong> Oncogene 23: 1789-1800, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14676839/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14676839</a>] [<a href="https://doi.org/10.1038/sj.onc.1207300" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14676839">Kang et al. (2004)</a> showed that human MDA5 was a general type I IFN-inducible gene with rapid temporal induction kinetics and limited basal expression in normal tissue. The JAK (see <a href="/entry/147795">147795</a>)/STAT (see <a href="/entry/600555">600555</a>) signaling pathway was directly involved in IFN-induced MDA5 expression. Overexpression of MDA5 induced apoptotic cell death in HO-1 melanoma cells. Mutation analysis showed that the CARD and ATPase domains of MDA5 were involved in cellular growth and survival. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14676839" 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="Colli, M. L., Moore, F., Gurzov, E. N., Ortis, F., Eizirik, D. L. <strong>MDA5 and PTPN2, two candidate genes for type 1 diabetes, modify pancreatic beta-cell responses to the viral by-product double-stranded RNA.</strong> Hum. Molec. Genet. 19: 135-146, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19825843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19825843</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19825843[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/10.1093/hmg/ddp474" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19825843">Colli et al. (2010)</a> evaluated whether modulation of MDA5 and PTPN2 (<a href="/entry/176887">176887</a>), 2 candidate genes for type 1 diabetes, affects beta-cell responses to double-stranded RNA (dsRNA), a by-product of viral replication. INS-1E cells and primary fluorescence-activated cell sorting-purified rat beta-cells were transfected with small interference RNAs (siRNAs) targeting MDA5 or PTPN2 and subsequently exposed to intracellular synthetic dsRNA polyinosinic-polycytidylic acid (PIC). PIC increased MDA5 and PTPN2 mRNA expression, which was inhibited by the specific siRNAs. PIC triggered apoptosis in INS-1E and primary beta-cells and this was augmented by PTPN2 knockdown, although inhibition of MDA5 did not modify PIC-induced apoptosis. In contrast, MDA5 silencing decreased PIC-induced cytokine and chemokine expression, although inhibition of PTPN2 induced minor or no changes in these inflammatory mediators. <a href="#7" class="mim-tip-reference" title="Colli, M. L., Moore, F., Gurzov, E. N., Ortis, F., Eizirik, D. L. <strong>MDA5 and PTPN2, two candidate genes for type 1 diabetes, modify pancreatic beta-cell responses to the viral by-product double-stranded RNA.</strong> Hum. Molec. Genet. 19: 135-146, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19825843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19825843</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19825843[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/10.1093/hmg/ddp474" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19825843">Colli et al. (2010)</a> concluded that changes in MDA5 and PTPN2 expression modify beta-cell responses to dsRNA. MDA5 regulates inflammatory signals, whereas PTPN2 may function as a defense mechanism against proapoptotic signals generated by dsRNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19825843" 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 the specific of RNA editing by ADAR1 (<a href="/entry/146920">146920</a>), <a href="#17" class="mim-tip-reference" title="Liddicoat, B. J., Piskol, R., Chalk, A. M., Ramaswami, G., Higuchi, M., Hartner, J. C., Li, J. B., Seeburg, P. H., Walkley, C. R. <strong>RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself.</strong> Science 349: 1115-1120, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26275108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26275108</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26275108[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.aac7049" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26275108">Liddicoat et al. (2015)</a> generated mice with an editing-deficient knockin mutation, Adar1(E861A). Adar1(E861A/E861A) embryos died at approximately embryonic day 13.5, with activated interferon (see <a href="/entry/147660">147660</a>) and dsRNA-sensing pathways. Genomewide analysis of the in vivo substrates of ADAR1 identified clustered hyperediting within long dsRNA stem loops within 3-prime untranslated regions of endogenous transcripts. Concurrent deletion of the cytosolic sensor of dsRNA MDA5 rescued embryonic death and other phenotypes of Adar1(E861A/E861A). <a href="#17" class="mim-tip-reference" title="Liddicoat, B. J., Piskol, R., Chalk, A. M., Ramaswami, G., Higuchi, M., Hartner, J. C., Li, J. B., Seeburg, P. H., Walkley, C. R. <strong>RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself.</strong> Science 349: 1115-1120, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26275108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26275108</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26275108[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.aac7049" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26275108">Liddicoat et al. (2015)</a> concluded that adenosine-to-inosine editing of endogenous dsRNA is the essential function of ADAR1, preventing the activation of the cytosolic dsRNA response by endogenous transcripts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26275108" 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="#18" class="mim-tip-reference" title="Motz, C., Schuhmann, K. M., Kirchhofer, A., Moldt, M., Witte, G., Conzelmann, K.-K., Hopfner, K.-P. <strong>Paramyxovirus V proteins disrupt the fold of the RNA sensor MDA5 to inhibit antiviral signaling.</strong> Science 339: 690-693, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23328395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23328395</a>] [<a href="https://doi.org/10.1126/science.1230949" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23328395">Motz et al. (2013)</a> determined the crystal structure of the MDA5 ATP-hydrolysis domain in complex with the viral inhibitor V protein. The V protein unfolded the ATP-hydrolysis domain of MDA5 via a beta-hairpin motif and recognized a structural motif of MDA5 that is normally buried in the conserved helicase fold. This leads to disruption of the MDA5 ATP-hydrolysis site and prevention of RNA-bound MDA5 filament formation. <a href="#18" class="mim-tip-reference" title="Motz, C., Schuhmann, K. M., Kirchhofer, A., Moldt, M., Witte, G., Conzelmann, K.-K., Hopfner, K.-P. <strong>Paramyxovirus V proteins disrupt the fold of the RNA sensor MDA5 to inhibit antiviral signaling.</strong> Science 339: 690-693, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23328395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23328395</a>] [<a href="https://doi.org/10.1126/science.1230949" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23328395">Motz et al. (2013)</a> explained why V proteins inactivate MDA5, but not RIGI (<a href="/entry/609631">609631</a>), and mutating only 2 amino acids in RIGI induces robust V protein binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23328395" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Singleton-Merten Syndrome 1</em></strong></p><p>
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In affected individuals from 3 unrelated families with early and extreme aortic and valvular calcification, dental anomalies, osteopenia, and acroosteolysis (SGMRT1; <a href="/entry/182250">182250</a>), <a href="#24" class="mim-tip-reference" title="Rutsch, F., MacDougall, M., Lu, C., Buers, I., Mamaeva, O., Nitschke, Y., Rice, G. I., Erlandsen, H., Kehl, H. G., Thiele, H., Nurnberg, P., Hohne, W., Crow, Y. J., Feigenbaum, A., Hennekam, R. C. <strong>A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome.</strong> Am. J. Hum. Genet. 96: 275-282, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25620204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25620204</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25620204[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2014.12.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25620204">Rutsch et al. (2015)</a> performed whole-exome sequencing and identified heterozygosity for a missense mutation in the IFIH1 gene (R822Q; <a href="#0009">606951.0009</a>) that segregated with disease in each family. Functional analysis demonstrated that R822Q is a gain-of-function substitution that triggers production of type 1 interferon, resulting in a heightened inflammatory state. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25620204" 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 French father with Singleton-Merten syndrome and his 2 affected sons with a variable neurologic presentation, <a href="#5" class="mim-tip-reference" title="Bursztejn, A.-C., Briggs, T. A., del Toro Duany, Y., Anderson, B. H., O'Sullivan, J., Williams, S. G., Bodemer, C., Fraitag, S., Gebhard, F., Leheup, B., Lemelle, I., Oojageer, A., Raffo, E., Schmitt, E., Rice, G. I., Hur, S., Crow, Y. J. <strong>Unusual cutaneous features associated with a heterozygous gain-of-function mutation in IFIH1: overlap between Aicardi-Goutieres and Singleton-Merten syndromes.</strong> Brit. J. Derm. 173: 1505-1513, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26284909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26284909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26284909[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1111/bjd.14073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26284909">Bursztejn et al. (2015)</a> identified heterozygosity for a missense mutation in the IFIH1 gene (A489T; <a href="#0015">606951.0015</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26284909" 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 5 affected individuals from 2 unrelated families with Singleton-Merten syndrome, <a href="#9" class="mim-tip-reference" title="de Carvalho, L. M., Ngoumou, G., Park, J. W., Ehmke, N., Deigendesch, N., Kitabayashi, N., Melki, I., Souza, F. F. L., Tzschach, A., Nogueira-Barbosa, M. H., Ferriani, V., Louzada-Junior, P., Marques, W., Lourenco, C. M., Horn, D., Kallinich, T., Stenzel, W., Hur, S., Rice, G. I., Crow, Y. J. <strong>Musculoskeletal disease in MDA5-related type I interferonopathy: a mendelian mimic of Jaccoud's arthropathy.</strong> Arthritis Rheumatol. 69: 2081-2091, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28605144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28605144</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28605144[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/10.1002/art.40179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28605144">de Carvalho et al. (2017)</a> sequenced the IFIH1 gene and identified heterozygosity for 2 different missense mutations at the same residue: a T331I substitution (<a href="#0016">606951.0016</a>) in family 1938, and a T331R substitution (<a href="#0017">606951.0017</a>) in family 1972. Both variants resulted in markedly increased levels of IFN signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28605144" 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 10-year-old boy with Singleton-Merten syndrome, <a href="#21" class="mim-tip-reference" title="Riou, M. C., de La Dure-Molla, M., Kerner, S., Rondeau, S., Legendre, A., Cormier-Daire, V., Fournier, B. P. J. <strong>Oral phenotype of Singleton-Merten syndrome: a systematic review illustrated with a case report.</strong> Front. Genet. 13: 875490, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35754802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35754802</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35754802[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/10.3389/fgene.2022.875490" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35754802">Riou et al. (2022)</a> identified heterozygosity for the recurrent R822Q mutation in the IFIH1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35754802" 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>Aicardi-Goutieres Syndrome 7</em></strong></p><p>
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In 8 probands with Aicardi-Goutieres syndrome 7 (AGS7; <a href="/entry/615846">615846</a>), <a href="#20" class="mim-tip-reference" title="Rice, G. I., del Toro Duany, Y., Jenkinson, E. M., Forte, G. M. A., Anderson, B. H., Ariaudo, G., Bader-Meunier, B., Baildam, E. M., Battini, R., Beresford, M. W., Casarano, M., Chouchane, M., and 41 others. <strong>Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling.</strong> Nature Genet. 46: 503-509, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24686847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24686847</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24686847[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.2933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24686847">Rice et al. (2014)</a> identified 6 different heterozygous mutations in the IFIH1 gene (<a href="#0001">606951.0001</a>-<a href="#0006">606951.0006</a>). The first 3 mutations were found by whole-exome sequencing. The mutations in 5 probands occurred de novo, whereas in 2 they were paternally transmitted; for 1 proband parental DNA was unavailable. In 1 family, 2 mutation carriers remained clinically unaffected as adults. In vitro functional expression assays in HEK293T cells showed that the mutations caused marked induction of interferon signaling in response to short 162-bp double-stranded RNA (dsRNA), whereas control cells did not. The mutations also conferred 4- to 10-fold higher levels of basal signaling activity even in the absence of exogenous ligand. The mutated residues were located on the surface of the RNA-binding and ATP-binding sites in conserved helicase domains, but ATP hydrolysis activity of the mutants was comparable to wildtype. Structural modeling and biochemical studies indicated that the mutations enhance the stability of the activated IFIH1 filament by increasing affinity for dsRNA. These findings were consistent with a gain of function, resulting in increased interferon signaling. The findings also suggested the presence of an undefined endogenous dsRNA capable of stimulating mutant receptors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24686847" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 unrelated Japanese patients with AGS7, <a href="#19" class="mim-tip-reference" title="Oda, H., Nakagawa, K., Abe, J., Awaya, T., Funabiki, M., Hijikata, A., Nishikomori, R., Funatsuka, M., Ohshima, Y., Sugawara, Y., Yasumi, T., Kato, H., Shirai, T., Ohara, O., Fujita, T., Heike, T. <strong>Aicardi-Goutieres syndrome is caused by IFIH1 mutations.</strong> Am. J. Hum. Genet. 95: 121-125, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24995871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24995871</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24995871[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2014.06.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24995871">Oda et al. (2014)</a> identified 3 different de novo heterozygous missense mutations in the IFIH1 gene (<a href="#0002">606951.0002</a>, <a href="#0007">606951.0007</a>, and <a href="#0008">606951.0008</a>). The mutations were found by trio-based whole-exome sequencing. Peripheral blood cells from the patients showed a type 1 interferon signature, and expression of each of the mutations in a human hepatoma cell line resulted in increased activation of the IFNB1 (<a href="/entry/147640">147640</a>) promoter compared to wildtype, consistent with increased type I interferon production. In vitro studies showed that the mutant IFIH1 proteins lacked ligand-specific responsiveness. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24995871" 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 6-year-old boy with bilateral spasticity, developmental delay, and basal ganglia calcification, <a href="#4" class="mim-tip-reference" title="Buers, I., Rice, G. I., Crow, Y. J., Rutsch, F. <strong>MDA5-associated neuroinflammation and the Singleton-Merten syndrome: two faces of the same type I interferonopathy spectrum.</strong> J. Interferon Cytokine Res. 37: 214-219, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28475458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28475458</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28475458[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/10.1089/jir.2017.0004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28475458">Buers et al. (2017)</a> identified heterozygosity for the recurrent R822Q mutation in the IFIH1 gene (<a href="#0009">606951.0009</a>), previously reported in patients with Singleton-Merten syndrome. The authors concluded that both diseases are part of an 'interferonopathy grouping,' and that the R822Q mutation can cause a spectrum of disease, including neurologic involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28475458" 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 female infant with AGS7, <a href="#2" class="mim-tip-reference" title="Amari, S., Tsukamoto, K., Ishiguro, A., Yanagi, K., Kaname, T., Ito, Y. <strong>An extremely severe case of Aicardi-Goutieres syndrome 7 with a novel variant in IFIH1.</strong> Europ. J. Med. Genet. 63: 103646, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30965144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30965144</a>] [<a href="https://doi.org/10.1016/j.ejmg.2019.04.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30965144">Amari et al. (2020)</a> identified a de novo heterozygous mutation in the IFIH1 gene (E813D; <a href="#0010">606951.0010</a>). The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30965144" 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>Immunodeficiency 95</em></strong></p><p>
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In a 5-year-old girl from Burma with immunodeficiency-95 (IMD95; <a href="/entry/619773">619773</a>), <a href="#16" class="mim-tip-reference" title="Lamborn, I. T., Jing, H., Zhang, Y., Drutman, S. B., Abbott, J. K., Munir, S., Bade, S., Murdock, H. M., Santos, C. P., Brock, L. G., Masutani, E., Fordjour, E. Y., and 14 others. <strong>Recurrent rhinovirus infections in a child with inherited MDA5 deficiency.</strong> J. Exp. Med. 214: 1949-1972, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28606988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28606988</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28606988[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20161759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28606988">Lamborn et al. (2017)</a>, identified a homozygous missense mutation in the IFIH1 gene (K365E; <a href="#0011">606951.0011</a>). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in the unaffected parents and brother. In vitro functional expression studies of patient cells and cells transfected with the mutation showed that the K365E mutant had minimal IFNB1 (<a href="/entry/147640">147640</a>) and NFKB (see <a href="/entry/164011">164011</a>) promoter activity after stimulation with poly(I:C) compared to wildtype. Cotransfection of the mutant with wildtype showed no dominant-negative effects; the findings were consistent with a loss of function. Cells with the mutation and cells with silencing of the IFIH1 gene demonstrated increased replication of human rhinovirus (HRV) and impaired interferon signaling compared to controls. However, these cells did not show increased viral replication of influenza or RSV. Transduction with wildtype, but not mutant, IFIH1 improved control of HRV replication. The findings were consistent with impaired viral recognition and antiviral responses specific for HRV. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28606988" 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 6-year-old girl, born of consanguineous Egyptian parents, with IMD95, <a href="#27" class="mim-tip-reference" title="Zaki, M., Thoenes, M., Kawalia, A., Nurnberg, P., Kaiser, R., Heller, R., Bolz, H. J. <strong>Recurrent and prolonged infections in a child with a homozygous IFIH1 nonsense mutation.</strong> Front. Genet. 8: 130, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29018476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29018476</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29018476[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/10.3389/fgene.2017.00130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29018476">Zaki et al. (2017)</a> identified a homozygous nonsense mutation in the IFIH1 gene (K889X; <a href="#0012">606951.0012</a>). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in the unaffected parents and sib. Western blot analysis of patient fibroblasts showed significantly decreased IFIH1 protein levels compared to controls, suggesting that the mutant transcript undergoes nonsense-mediated mRNA decay and results in a loss of function. In addition to IMD95, manifest as recurrent severe viral respiratory infections and persistent EBV infection, the patient also had a severe neurodevelopmental disorder with seizures and microcephaly associated with a homozygous missense mutation in the PHGDH gene (V425M; <a href="/entry/606879#0002">606879.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29018476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3-year-old girl (patient 1), born of consanguineous Moroccan parents, with IMD95, <a href="#6" class="mim-tip-reference" title="Cananzi, M., Wohler, E., Marzollo, A., Colavito, D., You, J., Jing, H., Bresolin, S., Gaio, P., Martin, R., Mescoli, C., Bade, S., Posey, J. E., and 18 others. <strong>IFIH1 loss-of-function variants contribute to very early-onset inflammatory bowel disease.</strong> Hum. Genet. 140: 1299-1312, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34185153/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34185153</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34185153[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/10.1007/s00439-021-02300-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34185153">Cananzi et al. (2021)</a> identified a homozygous frameshift mutation in the IFIH1 gene (<a href="#0013">606951.0013</a>). It was predicted to result in nonsense-mediated mRNA decay or produce a truncated protein lacking important functional domains. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each unaffected parent. In vitro functional studies using a luciferase reporter assay showed that mutant IFIH1 failed to activate the IFNB1 (<a href="/entry/147640">147640</a>) promoter following stimulation, consistent with a loss-of-function effect. In addition to recurrent and severe infections, including with CMV, the patient also had very early-onset inflammatory bowel disease (VEOIBD) in the first weeks of life. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34185153" 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 girl (PRI_022) with IMD95, <a href="#3" class="mim-tip-reference" title="Asgari, S., Schlapbach, L. J., Anchisi, S., Hammer, C., Bartha, I., Junier, T., Mottet-Osman, G., Posfay-Barbe, K. M., Longchamp, D., Stocker, M., Cordey, S., Kaiser, and 9 others. <strong>Severe viral respiratory infections in children with IFIH1 loss-of-function mutations.</strong> Proc. Nat. Acad. Sci. 114: 8342-8347, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28716935/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28716935</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28716935[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.1704259114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28716935">Asgari et al. (2017)</a> identified a homozygous splice site mutation in the IFIH1 gene (<a href="#0014">606951.0014</a>). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present at a low frequency in the gnomAD database (0.64%), including 7 homozygotes. Western blot analysis of patient cells showed that the mutant protein was expressed upon in vitro RSV infection. In vitro functional expression studies in HEK293T cells transfected with the mutation showed that the mutant protein was unstable, failed to lead to IFNB1 (<a href="/entry/147640">147640</a>) production, and had no detectable ATPase activity compared to wildtype, consistent with a loss-of-function effect. There was also evidence for a dominant-negative effect on the wildtype protein. Additional in vitro studies showed that RSV and HRV replication levels were increased in cells transduced with the mutation, indicating a central role for IFIH1 in innate immune recognition of RSV and HRV and in controlling these infections. Three additional children with severe early-onset viral HRC or RSV respiratory infections were heterozygous for the splice site variant and 4 further children were heterozygous for other loss-of-function variants in the IFIH1 gene, suggesting that heterozygosity may confer susceptibility to the disease. However, carrier parents were unaffected. The patients were part of a cohort of 120 children with severe manifestations of common viral respiratory infections who underwent exome sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28716935" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between variation in the IFIH1 gene and type 1 diabetes, see IDDM19 (<a href="/entry/610155">610155</a>).</p><p>For discussion of a possible association between variation in the IFIH1 gene and Graves disease, see <a href="/entry/275000">275000</a>.</p><p>For discussion of a possible association between variation in the IFIH1 gene and selective immunoglobulin A deficiency, see IGAD1 (<a href="/entry/137100">137100</a>).</p><p><a href="#22" class="mim-tip-reference" title="Robinson, T., Kariuki, S. N., Franek, B. S., Kumabe, M., Kumar, A. A., Badaracco, M., Mikolaitis, R. A., Guerrero, G., Utset, T. O., Drevlow, B. E., Zaacks, L. S., Grober, J. S., Cohen, L. M., Kirou, K. A., Crow, M. K., Jolly, M., Niewold, T. B. <strong>Autoimmune disease risk variant of IFIH1 is associated with increased sensitivity to IFN-alpha and serologic autoimmunity in lupus patients.</strong> J. Immun. 187: 1298-1303, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21705624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21705624</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21705624[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/10.4049/jimmunol.1100857" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21705624">Robinson et al. (2011)</a> studied the impact of the IFIH1 946A-T SNP (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1990760;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1990760</a>) in 563 American patients of various ethnicities with systemic lupus erythematosus (SLE; <a href="/entry/152700">152700</a>). They found that the T allele of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1990760;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1990760</a> was associated with anti-double-stranded DNA (dsDNA) antibodies in all groups, and that, among those with anti-dsDNA antibodies, the T allele was associated with lower serum IFNA. The T allele was also associated with increased IFN-induced gene expression in peripheral blood mononuclear cells in response to serum IFNA in anti-dsDNA antibody-positive patients, independent of the STAT4 (<a href="/entry/600558">600558</a>) genotype. <a href="#22" class="mim-tip-reference" title="Robinson, T., Kariuki, S. N., Franek, B. S., Kumabe, M., Kumar, A. A., Badaracco, M., Mikolaitis, R. A., Guerrero, G., Utset, T. O., Drevlow, B. E., Zaacks, L. S., Grober, J. S., Cohen, L. M., Kirou, K. A., Crow, M. K., Jolly, M., Niewold, T. B. <strong>Autoimmune disease risk variant of IFIH1 is associated with increased sensitivity to IFN-alpha and serologic autoimmunity in lupus patients.</strong> J. Immun. 187: 1298-1303, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21705624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21705624</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21705624[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/10.4049/jimmunol.1100857" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21705624">Robinson et al. (2011)</a> suggested that the T allele of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1990760;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1990760</a> may have a role in SLE pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21705624" 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="Gorman, J. A., Hundhausen, C., Errett, J. S., Stone, A. E., Allenspach, E. J., Ge, Y., Arkatkar, T., Clough, C., Dai, X., Khim, S., Pestal, K., Liggitt, D., Cerosaletti, K., Stetson, D. B., James, R. G., Oukka, M., Concannon, P., Gale, M., Buckner, J. H., Rawlings, D. J. <strong>The A946T variant of the RNA sensor IFIH1 mediates an interferon program that limits viral infection but increases the risk for autoimmunity.</strong> Nature Immun. 18: 744-752, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28553952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28553952</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28553952[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/ni.3766" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28553952">Gorman et al. (2017)</a> noted that the 946A-T variant has been associated with multiple autoimmune diseases. The authors found that peripheral blood mononuclear cells (PBMCs) from healthy donors with the 946A-T variant had increased interferon production in response to the ligand poly(I:C). Homozygotes also had significantly increased expression of interferon-stimulated genes. The authors showed that mice with a knockin 946A-T variant had increased basal interferon expression and better survived a viral challenge but had autoimmunity-related phenotypes including increased risk of diabetes and lupus. The authors suggested that survival of the variant in human populations is likely a case of balanced selection between response to viral infection versus risks from autoimmune diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28553952" 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 7 unrelated patients (patients 2-8) of various ethnic origins with very early-onset inflammatory bowel disease (VEOIBD), <a href="#6" class="mim-tip-reference" title="Cananzi, M., Wohler, E., Marzollo, A., Colavito, D., You, J., Jing, H., Bresolin, S., Gaio, P., Martin, R., Mescoli, C., Bade, S., Posey, J. E., and 18 others. <strong>IFIH1 loss-of-function variants contribute to very early-onset inflammatory bowel disease.</strong> Hum. Genet. 140: 1299-1312, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34185153/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34185153</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34185153[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/10.1007/s00439-021-02300-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34185153">Cananzi et al. (2021)</a> identified heterozygous loss-of-function variants in the IFIH1 gene (see, e.g., <a href="#0014">606951.0014</a>). The variants, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were present at low frequencies in the gnomAD database. There were 2 nonsense, 1 frameshift, and 1 splice site variant. The variants were inherited from an unaffected parent in 6 cases, consistent with incomplete penetrance and suggesting that the variants may confer susceptibility to the disease. The patients were diagnosed with Crohn disease (4), ulcerative colitis (2), and IBD with diffuse colonic nodular lymphatic hyperplasia (1). The median age at onset was 24 months (range, 3 months to 6 years), and the patients presented with bloody, mucous, protein-losing inflammatory diarrhea and poor overall growth. Colonoscopy showed multiple linear deep ulcers separated by skip areas of normal mucosa, and histology showed ileal and colonic inflammation with villous atrophy, crypt distortion, mucinous hyperplasia of colonocytes, and Paneth cell metaplasia. Laboratory studies showed elevated inflammatory markers such as ESR and CRP, anemia, and hypoalbuminemia. <a href="#6" class="mim-tip-reference" title="Cananzi, M., Wohler, E., Marzollo, A., Colavito, D., You, J., Jing, H., Bresolin, S., Gaio, P., Martin, R., Mescoli, C., Bade, S., Posey, J. E., and 18 others. <strong>IFIH1 loss-of-function variants contribute to very early-onset inflammatory bowel disease.</strong> Hum. Genet. 140: 1299-1312, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34185153/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34185153</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34185153[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/10.1007/s00439-021-02300-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34185153">Cananzi et al. (2021)</a> proposed that compromised microbacterial sensing due to the variants impairs IFIH1 activation and interferon production, leading to impairment of innate immune defenses and chronic intestinal inflammation. Additional environmental and genetic factors likely modify the risk of developing the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34185153" 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>Using mice deficient in MDA5, <a href="#15" class="mim-tip-reference" title="Kato, H., Takeuchi, O., Sato, S., Yoneyama, M., Yamamoto, M., Matsui, K., Uematsu, S., Jung, A., Kawai, T., Ishii, K. J., Yamaguchi, O., Otsu, K., Tsujimura, T., Koh, C.-S., Sousa, C. R., Matsuura, Y., Fujita, T., Akira, S. <strong>Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses.</strong> Nature 441: 101-105, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16625202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16625202</a>] [<a href="https://doi.org/10.1038/nature04734" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16625202">Kato et al. (2006)</a> showed that MDA5 and RIGI (<a href="/entry/609631">609631</a>) recognize different types of double-stranded RNAs: MDA5 recognizes PIC and RIGI detects in vitro transcribed double-stranded RNAs. RNA viruses are also differentially recognized by RIGI and MDA5. <a href="#15" class="mim-tip-reference" title="Kato, H., Takeuchi, O., Sato, S., Yoneyama, M., Yamamoto, M., Matsui, K., Uematsu, S., Jung, A., Kawai, T., Ishii, K. J., Yamaguchi, O., Otsu, K., Tsujimura, T., Koh, C.-S., Sousa, C. R., Matsuura, Y., Fujita, T., Akira, S. <strong>Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses.</strong> Nature 441: 101-105, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16625202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16625202</a>] [<a href="https://doi.org/10.1038/nature04734" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16625202">Kato et al. (2006)</a> found that RIGI is essential for the production of interferons in response to RNA viruses including paramyxoviruses, influenza virus, and Japanese encephalitis virus, whereas MDA5 is critical for picornavirus detection. Furthermore, Rig1-null and Mda5-null mice are highly susceptible to infection with these respective RNA viruses compared to control mice. <a href="#15" class="mim-tip-reference" title="Kato, H., Takeuchi, O., Sato, S., Yoneyama, M., Yamamoto, M., Matsui, K., Uematsu, S., Jung, A., Kawai, T., Ishii, K. J., Yamaguchi, O., Otsu, K., Tsujimura, T., Koh, C.-S., Sousa, C. R., Matsuura, Y., Fujita, T., Akira, S. <strong>Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses.</strong> Nature 441: 101-105, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16625202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16625202</a>] [<a href="https://doi.org/10.1038/nature04734" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16625202">Kato et al. (2006)</a> concluded that, taken together, their data show that RIGI and MDA5 distinguish different RNA viruses and are critical for host antiviral responses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16625202" 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 chemical mutagenesis, <a href="#11" class="mim-tip-reference" title="Funabiki, M., Kato, H., Miyachi, Y., Toki, H., Motegi, H., Inoue, M., Minowa, O., Yoshida, A., Deguchi, K., Sato, H., Ito, S., Shiroishi, T., Takeyasu, K., Noda, T., Fujita, T. <strong>Autoimmune disorders associated with gain of function of the intracellular sensor MDA5.</strong> Immunity 40: 199-212, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24530055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24530055</a>] [<a href="https://doi.org/10.1016/j.immuni.2013.12.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24530055">Funabiki et al. (2014)</a> generated mice with a mutation in exon 13 of Mda5, resulting in a gly821-to-ser (G821S) substitution. These mice spontaneously developed lupus-like nephritis and systemic autoimmune symptoms without viral infection. Mutant mice that also lacked Mavs failed to develop nephritis, and mutant mice that also lacked Ifnar1 (<a href="/entry/107450">107450</a>) had a partially ameliorated nephritis. The G821S mutant could activate signaling in the absence of its ligand, but it was defective for ligand- and virus-induced signaling, suggesting a possible conformational change in Mda5. <a href="#11" class="mim-tip-reference" title="Funabiki, M., Kato, H., Miyachi, Y., Toki, H., Motegi, H., Inoue, M., Minowa, O., Yoshida, A., Deguchi, K., Sato, H., Ito, S., Shiroishi, T., Takeyasu, K., Noda, T., Fujita, T. <strong>Autoimmune disorders associated with gain of function of the intracellular sensor MDA5.</strong> Immunity 40: 199-212, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24530055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24530055</a>] [<a href="https://doi.org/10.1016/j.immuni.2013.12.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24530055">Funabiki et al. (2014)</a> concluded that dysregulation of the innate immune sensor MDA5 causes autoimmune disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24530055" 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="#25" class="mim-tip-reference" title="Soda, N., Sakai, N., Kato, H., Takami, M., Fujita, T. <strong>Singleton-Merten syndrome-like skeletal abnormalities in mice with constitutively activated MDA5.</strong> J. Immun. 203: 1356-1368, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31366715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31366715</a>] [<a href="https://doi.org/10.4049/jimmunol.1900354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31366715">Soda et al. (2019)</a> found that mice with the constitutively active Mda5 G821S mutation exhibited growth retardation and decreased bone mineralization due to attenuated bone formation from osteoblasts and bone resorption by osteoclasts. The Mda5 G821S mutation did not intrinsically affect osteoclast function, but osteoclast differentiation from osteoclast precursor cells was extrinsically affected by exogenous type I Ifn that was induced by Mda5/Mavs signaling and played a central role in abnormal bone metabolism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31366715" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=606951[MIM]" class="btn btn-default mim-tip-hint" role="button" 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>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587777445 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777445;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=rs587777445" 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=rs587777445" 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=RCV000125470 OR RCV001849907 OR RCV004558317" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000125470, RCV001849907, RCV004558317" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000125470...</a>
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<p>In 2 unrelated patients of European descent with Aicardi-Goutieres syndrome-7 (AGS7; <a href="/entry/615846">615846</a>), <a href="#20" class="mim-tip-reference" title="Rice, G. I., del Toro Duany, Y., Jenkinson, E. M., Forte, G. M. A., Anderson, B. H., Ariaudo, G., Bader-Meunier, B., Baildam, E. M., Battini, R., Beresford, M. W., Casarano, M., Chouchane, M., and 41 others. <strong>Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling.</strong> Nature Genet. 46: 503-509, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24686847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24686847</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24686847[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.2933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24686847">Rice et al. (2014)</a> identified a de novo heterozygous c.2159G-A transition in exon 11 of the IFIH1 gene, resulting in an arg720-to-gln (R720Q) substitution at a highly conserved residue in the core helicase-2 domain. The mutation in the first patient was found by whole-exome sequencing and confirmed by Sanger sequencing. It was not present in the Exome Sequencing Project database or in over 300 in-house control exomes. In vitro functional expression assays in HEK293T cells showed that the mutation caused marked induction of interferon signaling in response to short 162-bp double-stranded RNA (dsRNA) compared to controls. The mutation conferred 4- to 10-fold higher levels of basal signaling activity even in the absence of exogenous ligand. These findings were consistent with a gain of function, resulting in increased interferon signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24686847" 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> rs587777446 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777446;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/rs587777446?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=rs587777446" 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=rs587777446" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 unrelated patients with Aicardi-Goutieres syndrome-7 (AGS7; <a href="/entry/615846">615846</a>), <a href="#20" class="mim-tip-reference" title="Rice, G. I., del Toro Duany, Y., Jenkinson, E. M., Forte, G. M. A., Anderson, B. H., Ariaudo, G., Bader-Meunier, B., Baildam, E. M., Battini, R., Beresford, M. W., Casarano, M., Chouchane, M., and 41 others. <strong>Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling.</strong> Nature Genet. 46: 503-509, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24686847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24686847</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24686847[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.2933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24686847">Rice et al. (2014)</a> identified a heterozygous c.2336G-A transition in exon 12 of the IFIH1 gene, resulting in an arg779-to-his (R779H) substitution at a highly conserved residue in the core helicase-2 domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the Exome Sequencing Project database or in over 300 in-house control exomes. The mutation occurred de novo in 1 patient. In the second family, the clinically asymptomatic father and paternal grandmother also carried the mutation, suggesting incomplete penetrance. However, all 3 mutation carriers in this family had a robust interferon signature. <a href="#20" class="mim-tip-reference" title="Rice, G. I., del Toro Duany, Y., Jenkinson, E. M., Forte, G. M. A., Anderson, B. H., Ariaudo, G., Bader-Meunier, B., Baildam, E. M., Battini, R., Beresford, M. W., Casarano, M., Chouchane, M., and 41 others. <strong>Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling.</strong> Nature Genet. 46: 503-509, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24686847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24686847</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24686847[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.2933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24686847">Rice et al. (2014)</a> suggested that the phenotypic variability in this family may have resulted from additional environmental or genetic factors. In vitro functional expression assays in HEK293T cells showed that the mutation caused marked induction of interferon signaling in response to short 162-bp double-stranded RNA (dsRNA) compared to controls. The mutation conferred 4- to 10-fold higher levels of basal signaling activity even in the absence of exogenous ligand. These findings were consistent with a gain of function, resulting in increased interferon signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24686847" 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="Oda, H., Nakagawa, K., Abe, J., Awaya, T., Funabiki, M., Hijikata, A., Nishikomori, R., Funatsuka, M., Ohshima, Y., Sugawara, Y., Yasumi, T., Kato, H., Shirai, T., Ohara, O., Fujita, T., Heike, T. <strong>Aicardi-Goutieres syndrome is caused by IFIH1 mutations.</strong> Am. J. Hum. Genet. 95: 121-125, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24995871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24995871</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24995871[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2014.06.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24995871">Oda et al. (2014)</a> identified a de novo heterozygous R779H mutation in a Japanese girl with AGS7. The mutation was found by trio-based whole-exome sequencing and confirmed by Sanger sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24995871" 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">rs587777447 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777447;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=rs587777447" 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=rs587777447" 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 European American patient with Aicardi-Goutieres syndrome-7 (AGS7; <a href="/entry/615846">615846</a>), <a href="#20" class="mim-tip-reference" title="Rice, G. I., del Toro Duany, Y., Jenkinson, E. M., Forte, G. M. A., Anderson, B. H., Ariaudo, G., Bader-Meunier, B., Baildam, E. M., Battini, R., Beresford, M. W., Casarano, M., Chouchane, M., and 41 others. <strong>Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling.</strong> Nature Genet. 46: 503-509, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24686847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24686847</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24686847[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.2933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24686847">Rice et al. (2014)</a> identified a de novo heterozygous c.1009A-G transition in exon 5 of the IFIH1 gene, resulting in an arg337-to-gly (R337G) substitution at a highly conserved residue in the core helicase-1 domain. The mutation was not found in the Exome Sequencing Project database or in over 300 in-house control exomes. In vitro functional expression assays in HEK293T cells showed that the mutation caused marked induction of interferon signaling in response to short 162-bp double-stranded RNA (dsRNA) compared to controls. The mutation conferred 4- to 10-fold higher levels of basal signaling activity even in the absence of exogenous ligand. These findings were consistent with a gain of function, resulting in increased interferon signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24686847" 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="#1" class="mim-tip-reference" title="Adang, L. A., Frank, D. B., Gilani, A., Takanohashi, A., Ulrick, N., Collins, A., Cross, Z., Galambos, C., Helman, G., Kanaan, U., Keller, S., Simon, D., Sherbini, O., Hanna, B. D., Vanderver, A. L. <strong>Aicardi goutieres syndrome is associated with pulmonary hypertension.</strong> Molec. Genet. Metab. 125: 351-358, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30219631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30219631</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30219631[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ymgme.2018.09.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30219631">Adang et al. (2018)</a> identified this mutation in a 16-year-old boy with AGS7 who died from cardiopulmonary arrest. Pulmonary hypertension was identified at autopsy. The mutation was shown to have occurred de novo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30219631" 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">rs587777448 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777448;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=rs587777448" 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=rs587777448" 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=RCV000125473 OR RCV000255113 OR RCV001382400" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000125473, RCV000255113, RCV001382400" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000125473...</a>
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<p>In a patient of British descent with Aicardi-Goutieres syndrome-7 (AGS7; <a href="/entry/615846">615846</a>), <a href="#20" class="mim-tip-reference" title="Rice, G. I., del Toro Duany, Y., Jenkinson, E. M., Forte, G. M. A., Anderson, B. H., Ariaudo, G., Bader-Meunier, B., Baildam, E. M., Battini, R., Beresford, M. W., Casarano, M., Chouchane, M., and 41 others. <strong>Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling.</strong> Nature Genet. 46: 503-509, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24686847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24686847</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24686847[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.2933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24686847">Rice et al. (2014)</a> identified a heterozygous c.2335C-T transition in exon 12 of the IFIH1 gene, resulting in an arg779-to-cys (R779C) substitution at a highly conserved residue in the core helicase-2 domain. The mutation was not found in the Exome Sequencing Project database or in over 300 in-house control exomes. In vitro functional expression assays in HEK293T cells showed that the mutation caused marked induction of interferon signaling in response to short 162-bp double-stranded RNA (dsRNA) compared to controls. The mutation conferred 4- to 10-fold higher levels of basal signaling activity even in the absence of exogenous ligand. These findings were consistent with a gain of function, resulting in increased interferon signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24686847" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 AICARDI-GOUTIERES SYNDROME 7</strong>
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IFIH1, GLY495ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs672601336 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs672601336;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=rs672601336" 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=rs672601336" 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=RCV000125474 OR RCV004812301" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000125474, RCV004812301" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000125474...</a>
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<p>In a British father and daughter (F524) with Aicardi-Goutieres syndrome-7 (AGS7; <a href="/entry/615846">615846</a>), <a href="#20" class="mim-tip-reference" title="Rice, G. I., del Toro Duany, Y., Jenkinson, E. M., Forte, G. M. A., Anderson, B. H., Ariaudo, G., Bader-Meunier, B., Baildam, E. M., Battini, R., Beresford, M. W., Casarano, M., Chouchane, M., and 41 others. <strong>Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling.</strong> Nature Genet. 46: 503-509, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24686847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24686847</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24686847[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.2933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24686847">Rice et al. (2014)</a> identified a heterozygous c.1483G-A transition in exon 7 of the IFIH1 gene, resulting in a gly495-to-arg (G495R) substitution at a conserved residue in the core helicase-1 domain. The mutation was not found in the Exome Sequencing Project database or in over 300 in-house control exomes. The mutation occurred de novo in the father. In vitro functional expression assays in HEK293T cells showed that the mutation caused marked induction of interferon signaling in response to short 162-bp double-stranded RNA (dsRNA) compared to controls. The mutation conferred 4- to 10-fold higher levels of basal signaling activity even in the absence of exogenous ligand. These findings were consistent with a gain of function, resulting in increased interferon signaling. The patients had a unique phenotype characterized mainly by early-onset spastic paraparesis; the daughter also developed had a multisystem inflammatory process with brain imaging abnormalities. The British father was also reported by <a href="#8" class="mim-tip-reference" title="Crow, Y. J., Zaki, M. S., Abdel-Hamid, M. S., Abdel-Salam, G., Boespflug-Tanguy, O., Cordeiro, N. J. V., Gleeson, J. G., Gowrinathan, N. R., Laugel, V., Renaldo, F., Rodriguez, D., Livingston, J. H., Rice, G. I. <strong>Mutations in ADAR1, IFIH1, and RNASEH2B presenting as spastic paraplegia.</strong> Neuropediatrics 45: 386-391, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25243380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25243380</a>] [<a href="https://doi.org/10.1055/s-0034-1389161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25243380">Crow et al. (2014)</a>. He had onset of motor symptoms around 2 years of age when he developed toe-walking and frequent falls after normal early development. He was diagnosed with cerebral palsy, but the disorder was slowly progressive. At age 33 years, he showed lower limb spasticity without upper limb involvement. Brain imaging and cognition were normal at the age of 29 years. Laboratory studies showed persistently increased interferon. <a href="#8" class="mim-tip-reference" title="Crow, Y. J., Zaki, M. S., Abdel-Hamid, M. S., Abdel-Salam, G., Boespflug-Tanguy, O., Cordeiro, N. J. V., Gleeson, J. G., Gowrinathan, N. R., Laugel, V., Renaldo, F., Rodriguez, D., Livingston, J. H., Rice, G. I. <strong>Mutations in ADAR1, IFIH1, and RNASEH2B presenting as spastic paraplegia.</strong> Neuropediatrics 45: 386-391, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25243380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25243380</a>] [<a href="https://doi.org/10.1055/s-0034-1389161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25243380">Crow et al. (2014)</a> emphasized the phenotypic variability associated with AGS, noting that neurologic dysfunction is not always marked in this disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25243380+24686847" 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 id="0006" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0006 AICARDI-GOUTIERES SYNDROME 7</strong>
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IFIH1, ASP393VAL
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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> rs587777449 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777449;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/rs587777449?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=rs587777449" 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=rs587777449" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000125475" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000125475" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000125475</a>
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<p>In an Italian patient with Aicardi-Goutieres syndrome-7 (AGS7; <a href="/entry/615846">615846</a>), <a href="#20" class="mim-tip-reference" title="Rice, G. I., del Toro Duany, Y., Jenkinson, E. M., Forte, G. M. A., Anderson, B. H., Ariaudo, G., Bader-Meunier, B., Baildam, E. M., Battini, R., Beresford, M. W., Casarano, M., Chouchane, M., and 41 others. <strong>Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling.</strong> Nature Genet. 46: 503-509, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24686847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24686847</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24686847[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.2933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24686847">Rice et al. (2014)</a> identified a de novo heterozygous c.1178A-T transversion in exon 6 of the IFIH1 gene, resulting in an asp393-to-val (D393V) substitution at a highly conserved residue in the core helicase-1 domain. The mutation was not found in the Exome Sequencing Project database or in over 300 in-house control exomes. In vitro functional expression assays in HEK293T cells showed that the mutation caused marked induction of interferon signaling in response to short 162-bp double-stranded RNA (dsRNA) compared to controls. The mutation conferred 4- to 10-fold higher levels of basal signaling activity even in the absence of exogenous ligand. These findings were consistent with a gain of function, resulting in increased interferon signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24686847" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 AICARDI-GOUTIERES SYNDROME 7</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587777575 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777575;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=rs587777575" 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=rs587777575" 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=RCV000128858" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000128858" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000128858</a>
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<p>In a Japanese boy with Aicardi-Goutieres syndrome-7 (AGS7; <a href="/entry/615846">615846</a>), <a href="#19" class="mim-tip-reference" title="Oda, H., Nakagawa, K., Abe, J., Awaya, T., Funabiki, M., Hijikata, A., Nishikomori, R., Funatsuka, M., Ohshima, Y., Sugawara, Y., Yasumi, T., Kato, H., Shirai, T., Ohara, O., Fujita, T., Heike, T. <strong>Aicardi-Goutieres syndrome is caused by IFIH1 mutations.</strong> Am. J. Hum. Genet. 95: 121-125, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24995871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24995871</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24995871[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2014.06.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24995871">Oda et al. (2014)</a> identified a de novo heterozygous c.1354G-A transition in the IFIH1 gene, resulting in an ala452-to-thr (A452T) substitution at a conserved residue in the helicase domain. The mutation, which was found by trio-based exome sequencing, was filtered against the dbSNP (build 137) database and was not present in an in-house exome database of 312 Japanese individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24995871" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 AICARDI-GOUTIERES SYNDROME 7</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587777576 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777576;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=rs587777576" 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=rs587777576" 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=RCV000128859" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000128859" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000128859</a>
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<p>In a Japanese boy with Aicardi-Goutieres syndrome-7 (AGS7; <a href="/entry/615846">615846</a>), <a href="#19" class="mim-tip-reference" title="Oda, H., Nakagawa, K., Abe, J., Awaya, T., Funabiki, M., Hijikata, A., Nishikomori, R., Funatsuka, M., Ohshima, Y., Sugawara, Y., Yasumi, T., Kato, H., Shirai, T., Ohara, O., Fujita, T., Heike, T. <strong>Aicardi-Goutieres syndrome is caused by IFIH1 mutations.</strong> Am. J. Hum. Genet. 95: 121-125, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24995871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24995871</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24995871[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2014.06.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24995871">Oda et al. (2014)</a> identified a de novo heterozygous c.1114C-T transition in the IFIH1 gene, resulting in a leu372-to-phe (L372F) substitution at a conserved residue in the helicase domain. The mutation, which was found by trio-based exome sequencing, was filtered against the dbSNP (build 137) database and was not present in an in-house exome database of 312 Japanese individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24995871" 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> rs376048533 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs376048533;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/rs376048533?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=rs376048533" 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=rs376048533" 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=RCV000169754 OR RCV000436896 OR RCV000789041 OR RCV000822311 OR RCV004745248" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000169754, RCV000436896, RCV000789041, RCV000822311, RCV004745248" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000169754...</a>
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<p><strong><em>Singleton-Merten Syndrome 1</em></strong></p><p>
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In affected individuals from 3 unrelated families with early and extreme aortic and valvular calcification, dental anomalies, osteopenia, and acroosteolysis (SGMRT1; <a href="/entry/182250">182250</a>), previously reported by <a href="#10" class="mim-tip-reference" title="Feigenbaum, A., Kumar, A., Weksberg, R. <strong>Singleton-Merten (S-M) syndrome: autosomal dominant transmission with variable expression. (Abstract)</strong> Am. J. Hum. Genet. 43: A48 only, 1988."None>Feigenbaum et al. (1988)</a>, <a href="#23" class="mim-tip-reference" title="Rutsch, F., Kehl, H. G., Ruf, N., Vogt, J., Kleinheinz, J., Rauch, F., Hofbauer, L. C., Rehder, H., Arslan-Kirchner, M., Nurnberg, P. <strong>Singleton-Merten syndrome: evidence of autosomal dominant inheritance in the first European family. (Abstract)</strong> Europ. J. Hum. Genet. 13: 112-113 (P0154), 2005."None>Rutsch et al. (2005)</a>, and <a href="#26" class="mim-tip-reference" title="Valverde, I., Rosenthal, E., Tzifa, A., Desai, P., Bell, A., Pushparajah, K., Qureshi, S., Beerbaum, P., Simpson, J. <strong>Singleton-Merten syndrome and impaired cardiac function.</strong> J. Am. Coll. Cardiol. 56: 1760 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21070929/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21070929</a>] [<a href="https://doi.org/10.1016/j.jacc.2010.02.078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21070929">Valverde et al. (2010)</a>, respectively, <a href="#24" class="mim-tip-reference" title="Rutsch, F., MacDougall, M., Lu, C., Buers, I., Mamaeva, O., Nitschke, Y., Rice, G. I., Erlandsen, H., Kehl, H. G., Thiele, H., Nurnberg, P., Hohne, W., Crow, Y. J., Feigenbaum, A., Hennekam, R. C. <strong>A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome.</strong> Am. J. Hum. Genet. 96: 275-282, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25620204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25620204</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25620204[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2014.12.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25620204">Rutsch et al. (2015)</a> performed whole-exome sequencing and identified heterozygosity for a c.2465G-A transition in the IFIH1 gene, resulting in an arg822-to-gln (R822Q) substitution at a highly conserved residue in 1 of 2 core helicase domains. The mutation, which segregated with disease in each family, was not found in any unaffected family members; analysis of 17 additional family members from the largest family showed that all but 1 individual with dental anomalies carried the mutation, and 1 individual with only psoriasis carried the mutation, whereas 3 others with only psoriasis did not. The authors noted that the IFIH1 c.2465G-A variant has been reported as a SNP (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs376048533;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs376048533</a>) in 1 individual with 'cardiac and pulmonary phenotypes' from among 6,517 individuals in the NHLBI Exome Variant Server database, and is listed in the Exome Aggregation Consortium Browser with an allele frequency of 0.00002481. In vitro functional analysis revealed that the R822Q mutant enhanced MDA5 function in interferon-beta (IFNB1; <a href="/entry/147640">147640</a>) induction, and interferon signature genes were upregulated in patient blood and dental cells. <a href="#24" class="mim-tip-reference" title="Rutsch, F., MacDougall, M., Lu, C., Buers, I., Mamaeva, O., Nitschke, Y., Rice, G. I., Erlandsen, H., Kehl, H. G., Thiele, H., Nurnberg, P., Hohne, W., Crow, Y. J., Feigenbaum, A., Hennekam, R. C. <strong>A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome.</strong> Am. J. Hum. Genet. 96: 275-282, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25620204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25620204</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25620204[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2014.12.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25620204">Rutsch et al. (2015)</a> concluded that R822Q is a gain-of-function substitution that causes Singleton-Merten syndrome through dysregulation of the human innate immune response. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25620204+21070929" 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 10-year-old boy with Singleton-Merten syndrome, <a href="#21" class="mim-tip-reference" title="Riou, M. C., de La Dure-Molla, M., Kerner, S., Rondeau, S., Legendre, A., Cormier-Daire, V., Fournier, B. P. J. <strong>Oral phenotype of Singleton-Merten syndrome: a systematic review illustrated with a case report.</strong> Front. Genet. 13: 875490, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35754802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35754802</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35754802[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/10.3389/fgene.2022.875490" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35754802">Riou et al. (2022)</a> identified heterozygosity for the recurrent R822Q mutation (c.2465G-A, NM_022168.4) in the IFIH1 gene. The mutation arose de novo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35754802" 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>Aicardi-Goutieres Syndrome 7</em></strong></p><p>
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In a 6-year-old boy with bilateral spasticity, developmental delay, and basal ganglia calcification (AGS7; <a href="/entry/615846">615846</a>), <a href="#4" class="mim-tip-reference" title="Buers, I., Rice, G. I., Crow, Y. J., Rutsch, F. <strong>MDA5-associated neuroinflammation and the Singleton-Merten syndrome: two faces of the same type I interferonopathy spectrum.</strong> J. Interferon Cytokine Res. 37: 214-219, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28475458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28475458</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28475458[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/10.1089/jir.2017.0004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28475458">Buers et al. (2017)</a> identified heterozygosity for the R822Q mutation in the IFIH1 gene. The mutation was not present in parental DNA and was considered to have arisen de novo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28475458" 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">rs1559810905 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1559810905;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=rs1559810905" 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=rs1559810905" 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=RCV000761569" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000761569" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000761569</a>
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<p>In a female infant with Aicardi-Goutieres syndrome-7 (AGS7; <a href="/entry/615846">615846</a>), <a href="#2" class="mim-tip-reference" title="Amari, S., Tsukamoto, K., Ishiguro, A., Yanagi, K., Kaname, T., Ito, Y. <strong>An extremely severe case of Aicardi-Goutieres syndrome 7 with a novel variant in IFIH1.</strong> Europ. J. Med. Genet. 63: 103646, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30965144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30965144</a>] [<a href="https://doi.org/10.1016/j.ejmg.2019.04.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30965144">Amari et al. (2020)</a> identified a de novo heterozygous c.2439A-T transversion (c.2439A-T, NM_022168) in exon 12 of the IFIH1 gene, resulting in a glu813-to-asp (E813D) substitution in the HEL2 domain. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. The mutation was not present in the gnomAD database or in an in-house database. Functional studies were not performed. The patient had prenatal findings including cardiomegaly, pericardial effusion, and intracranial calcifications. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30965144" 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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IFIH1, LYS365GLU (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs117608083;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs117608083</a>)
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001517044 OR RCV001843590" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001517044, RCV001843590" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001517044...</a>
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<p>In a 5-year-old girl from Burma with immunodeficiency-95 (IMD95; <a href="/entry/619773">619773</a>), <a href="#16" class="mim-tip-reference" title="Lamborn, I. T., Jing, H., Zhang, Y., Drutman, S. B., Abbott, J. K., Munir, S., Bade, S., Murdock, H. M., Santos, C. P., Brock, L. G., Masutani, E., Fordjour, E. Y., and 14 others. <strong>Recurrent rhinovirus infections in a child with inherited MDA5 deficiency.</strong> J. Exp. Med. 214: 1949-1972, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28606988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28606988</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28606988[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20161759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28606988">Lamborn et al. (2017)</a>, identified a homozygous c.1093A-G transition (c.1093A-G, NM_022168.3) in the IFIH1 gene, resulting in a lys365-to-glu (K365E) substitution at a conserved residue in the Hel1 domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was found at a low frequency in the ExAC database (0.06%) only in the heterozygous state and mainly in Asian populations. Both unaffected parents and an unaffected brother were heterozygous for the mutation. Patient cells showed normal protein levels, but the mutant protein was unable to bind to the poly(I:C) ligand, suggesting improper assembly and impaired downstream signaling. In vitro functional expression studies using a luciferase reporter assay demonstrated that the K365E mutant had minimal IFNB1 (<a href="/entry/147640">147640</a>) and NFKB (see <a href="/entry/164011">164011</a>) promoter activity after stimulation with poly(I:C) compared to wildtype. Cotransfection of the mutant with wildtype showed no dominant-negative effects; the findings were consistent with a loss of function. Increased human rhinovirus (HRV) replication was observed in patient primary respiratory nasal epithelial cells compared to controls. However, these cells did not show increased viral replication of influenza or RSV. Similarly, silencing of IFIH1 in a respiratory epithelial cell line resulted in increased HRV transcripts, increased production of infectious virus, and decreased levels of IFN-regulated transcripts after HRV infection compared to controls, consistent with impaired viral recognition and antiviral responses. Transduction with wildtype, but not mutant, IFIH1 improved control of HRV replication. Similar to patient cells, silencing of IFIH1 did not increase replication of influenza or RSV in vitro. Overall, these findings indicated that IFIH1 has a nonredundant role in immunity against respiratory infections specifically caused by HRV. The patient had early-onset recurrent viral respiratory infections often requiring hospitalization. She also carried a heterozygous 4-bp deletion in the TM4SF20 gene (<a href="/entry/615404#0001">615404.0001</a>) that likely explained her delays in motor and language development. Genetic analysis also identified 14 other homozygous missense mutations, 2 compound heterozygous missense mutations, and 3 de novo missense mutations, but the IFIH1 mutation was computationally predicted and functionally demonstrated to be deleterious. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28606988" 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> rs1252022173 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1252022173;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/rs1252022173?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=rs1252022173" 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=rs1252022173" 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 6-year-old girl, born of consanguineous Egyptian parents, with immunodeficiency-95 (IMD95; <a href="/entry/619773">619773</a>), <a href="#27" class="mim-tip-reference" title="Zaki, M., Thoenes, M., Kawalia, A., Nurnberg, P., Kaiser, R., Heller, R., Bolz, H. J. <strong>Recurrent and prolonged infections in a child with a homozygous IFIH1 nonsense mutation.</strong> Front. Genet. 8: 130, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29018476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29018476</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29018476[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/10.3389/fgene.2017.00130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29018476">Zaki et al. (2017)</a> identified a homozygous c.2665A-T transversion (c.2665A-T, NM_022168.2) in exon 14 of the IFIH1 gene, resulting in a lys889-to-ter (K889X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in the unaffected parents and sib. It was not present in the ExAC or 1TGP databases. Western blot analysis of patient fibroblasts showed significantly decreased IFIH1 protein levels compared to controls, suggesting that the mutant transcript undergoes nonsense-mediated mRNA decay and results in a loss of function. In addition to IMD95, manifest as recurrent severe viral respiratory infections and persistent EBV infection, the patient also had a severe neurodevelopmental disorder with seizures and microcephaly associated with a homozygous missense mutation in the PHGDH gene (V425M; <a href="/entry/606879#0002">606879.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29018476" 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> rs773033563 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs773033563;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/rs773033563?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=rs773033563" 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=rs773033563" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 3-year-old girl (patient 1), born of consanguineous Moroccan parents, with immunodeficiency-95 (IMD95; <a href="/entry/619773">619773</a>), <a href="#6" class="mim-tip-reference" title="Cananzi, M., Wohler, E., Marzollo, A., Colavito, D., You, J., Jing, H., Bresolin, S., Gaio, P., Martin, R., Mescoli, C., Bade, S., Posey, J. E., and 18 others. <strong>IFIH1 loss-of-function variants contribute to very early-onset inflammatory bowel disease.</strong> Hum. Genet. 140: 1299-1312, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34185153/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34185153</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34185153[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/10.1007/s00439-021-02300-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34185153">Cananzi et al. (2021)</a> identified a homozygous 1-bp deletion (c.2016delA, NM_022168) in exon 10 of the IFIH1 gene, resulting in a frameshift and premature termination (Asp673IlefsTer5) in the Hel2i domain. It was predicted to result in nonsense-mediated mRNA decay or produce a truncated protein lacking important functional domains. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each unaffected parent. The mutation was found at a low frequency in the gnomAD database (2.99 x 10(-4)). In vitro functional studies using a luciferase reporter assay showed that mutant IFIH1 failed to activate the IFNB1 (<a href="/entry/147640">147640</a>) promoter following stimulation, consistent with a loss-of-function effect. In addition to recurrent and severe infections, including with CMV, the patient also had very early-onset inflammatory bowel disease (VEOIBD) in the first weeks of life. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34185153" 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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IFIH1, IVS14DS, G-A, +1 (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs35732034;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs35732034</a>)
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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> rs35732034 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs35732034;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/rs35732034?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=rs35732034" 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=rs35732034" 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=RCV000652102 OR RCV001775941 OR RCV001844209 OR RCV002499122 OR RCV003447548 OR RCV003918068" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000652102, RCV001775941, RCV001844209, RCV002499122, RCV003447548, RCV003918068" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000652102...</a>
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<p>In a 16-month-old girl (PRI_022) with immunodeficiency-95 (IMD95; <a href="/entry/619773">619773</a>), <a href="#3" class="mim-tip-reference" title="Asgari, S., Schlapbach, L. J., Anchisi, S., Hammer, C., Bartha, I., Junier, T., Mottet-Osman, G., Posfay-Barbe, K. M., Longchamp, D., Stocker, M., Cordey, S., Kaiser, and 9 others. <strong>Severe viral respiratory infections in children with IFIH1 loss-of-function mutations.</strong> Proc. Nat. Acad. Sci. 114: 8342-8347, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28716935/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28716935</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28716935[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.1704259114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28716935">Asgari et al. (2017)</a> identified a homozygous splice site mutation in the IFIH1 gene, resulting in a splicing defect, the skipping of exon 14, a frameshift, and premature termination (Ile872Ter). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present at a low frequency in the gnomAD database (0.64%). The mutation was inherited from her unaffected parents. In vitro functional expression studies in HEK293T cells transfected with the mutation showed that the mutant protein was unstable, failed to lead to IFNB1 (<a href="/entry/147640">147640</a>) production, and had no detectable ATPase activity compared to wildtype, consistent with a loss-of-function effect. There was also evidence for a dominant-negative effect on the wildtype protein. Additional in vitro studies showed that RSV and HRV replication levels were increased in cells transduced with the mutation, indicating a central role for IFIH1 in innate immune recognition of RSV and HRV and in controlling these infections. The patient presented with early-onset respiratory failure associated with RSV infection. Three additional children with severe early-onset viral HRC or RSV respiratory infections were heterozygous for the splice site variant; however, 2 patient inherited the variant from an unaffected parent. These findings suggested that heterozygosity for loss-of-function IFIH1 variants may confer susceptibility to the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28716935" 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>Association Pending Confirmation</em></strong></p><p>
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In 2 unrelated patients (P3 and P7) with very early-onset inflammatory bowel disease (VEOIBD), <a href="#6" class="mim-tip-reference" title="Cananzi, M., Wohler, E., Marzollo, A., Colavito, D., You, J., Jing, H., Bresolin, S., Gaio, P., Martin, R., Mescoli, C., Bade, S., Posey, J. E., and 18 others. <strong>IFIH1 loss-of-function variants contribute to very early-onset inflammatory bowel disease.</strong> Hum. Genet. 140: 1299-1312, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34185153/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34185153</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34185153[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/10.1007/s00439-021-02300-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34185153">Cananzi et al. (2021)</a> identified the same intron 14 splice site mutation (c.2807+1G-A, NM_022168) in heterozygous state. This variant, which was identified by whole-exome sequencing, was inherited from an unaffected parent in both families, suggesting incomplete penetrance. In vitro functional expression studies using a luciferase reporter assay showed that the variant IFIH1 failed to activate the IFNB1 promoter following stimulation, consistent with a loss-of-function effect. Both patients with VEOIBD and the c.2807+1G-A mutation also carried an inherited T702I missense variant (one in trans, the other in cis) in the IFIH1 gene that had no functional effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34185153" 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">rs1576226604 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1576226604;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=rs1576226604" 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=rs1576226604" 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=RCV001003356 OR RCV003234569" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001003356, RCV003234569" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001003356...</a>
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<p>In a French father and 2 sons with Singleton-Merten syndrome (SGMRT1; <a href="/entry/182250">182250</a>), <a href="#5" class="mim-tip-reference" title="Bursztejn, A.-C., Briggs, T. A., del Toro Duany, Y., Anderson, B. H., O'Sullivan, J., Williams, S. G., Bodemer, C., Fraitag, S., Gebhard, F., Leheup, B., Lemelle, I., Oojageer, A., Raffo, E., Schmitt, E., Rice, G. I., Hur, S., Crow, Y. J. <strong>Unusual cutaneous features associated with a heterozygous gain-of-function mutation in IFIH1: overlap between Aicardi-Goutieres and Singleton-Merten syndromes.</strong> Brit. J. Derm. 173: 1505-1513, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26284909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26284909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26284909[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1111/bjd.14073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26284909">Bursztejn et al. (2015)</a> identified heterozygosity for a c.1465G-A transition in the IFIH1 gene, resulting in an ala489-to-thr (A489T) substitution at a highly conserved residue within the core helicase Hel1 domain. The mutation, which was not found in the ExAC database, was also not present in the paternal grandparents, indicating a de novo origin or gonadal mosaicism. The A489T mutant showed impaired ATP hydrolysis activity compared to wildtype IFIH1, and the mutant protein-RNA complex showed increased stability in the presence of ATP compared to wildtype. Analysis of transfected HEK293T cells revealed that basal levels of interferon signaling were markedly increased in the absence of exogenous RNA with the A489T mutant. In addition, mutant IFIH1 displayed marked interferon induction following stimulation with either long or short double-stranded RNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26284909" 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>.0016 SINGLETON-MERTEN SYNDROME 1</strong>
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IFIH1, THR331ILE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1576229572 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1576229572;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=rs1576229572" 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=rs1576229572" 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=RCV001003351 OR RCV003234568" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001003351, RCV003234568" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001003351...</a>
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<p>In an 18-year-old girl, her mother, and maternal aunt (family 1938) with Singleton-Merten syndrome (SGMRT1; <a href="/entry/182250">182250</a>), <a href="#9" class="mim-tip-reference" title="de Carvalho, L. M., Ngoumou, G., Park, J. W., Ehmke, N., Deigendesch, N., Kitabayashi, N., Melki, I., Souza, F. F. L., Tzschach, A., Nogueira-Barbosa, M. H., Ferriani, V., Louzada-Junior, P., Marques, W., Lourenco, C. M., Horn, D., Kallinich, T., Stenzel, W., Hur, S., Rice, G. I., Crow, Y. J. <strong>Musculoskeletal disease in MDA5-related type I interferonopathy: a mendelian mimic of Jaccoud's arthropathy.</strong> Arthritis Rheumatol. 69: 2081-2091, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28605144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28605144</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28605144[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/10.1002/art.40179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28605144">de Carvalho et al. (2017)</a> identified heterozygosity for a c.992C-T transition (c.992C-T, NM_022168) in the IFIH1 gene, resulting in a thr331-to-ile (T331I) substitution at a highly conserved residue within the Hel1 core helicase domain. Familial segregation was not reported. The variant was not found in the ExAC database. Studies in HEK293T cells showed that basal levels of IFN signaling were markedly increased with the T331I mutant in the absence of endogenous dsRNA ligand, consistent with constitutive activation of MDA5. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28605144" 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>.0017 SINGLETON-MERTEN SYNDROME 1</strong>
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IFIH1, THR331ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1576229572 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1576229572;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=rs1576229572" 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=rs1576229572" 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=RCV001003350 OR RCV003234567" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001003350, RCV003234567" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001003350...</a>
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<p>In a 9-year-old girl and her affected father (family 1972) with Singleton-Merten syndrome (SGMRT1; <a href="/entry/182250">182250</a>), <a href="#9" class="mim-tip-reference" title="de Carvalho, L. M., Ngoumou, G., Park, J. W., Ehmke, N., Deigendesch, N., Kitabayashi, N., Melki, I., Souza, F. F. L., Tzschach, A., Nogueira-Barbosa, M. H., Ferriani, V., Louzada-Junior, P., Marques, W., Lourenco, C. M., Horn, D., Kallinich, T., Stenzel, W., Hur, S., Rice, G. I., Crow, Y. J. <strong>Musculoskeletal disease in MDA5-related type I interferonopathy: a mendelian mimic of Jaccoud's arthropathy.</strong> Arthritis Rheumatol. 69: 2081-2091, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28605144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28605144</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28605144[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/10.1002/art.40179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28605144">de Carvalho et al. (2017)</a> identified heterozygosity for a c.992C-G transition (c.992C-G, NM_022168) in the IFIH1 gene, resulting in a thr331-to-arg (T331R) substitution at a highly conserved residue within the Hel1 core helicase domain. Familial segregation was not reported. The variant was not found in the ExAC database. Studies in HEK293T cells showed that basal levels of IFN signaling were markedly increased with the T331R mutant in the absence of endogenous dsRNA ligand, consistent with constitutive activation of MDA5. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28605144" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Adang2018" class="mim-anchor"></a>
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Adang, L. A., Frank, D. B., Gilani, A., Takanohashi, A., Ulrick, N., Collins, A., Cross, Z., Galambos, C., Helman, G., Kanaan, U., Keller, S., Simon, D., Sherbini, O., Hanna, B. D., Vanderver, A. L.
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<strong>Aicardi goutieres syndrome is associated with pulmonary hypertension.</strong>
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Molec. Genet. Metab. 125: 351-358, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30219631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30219631</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30219631[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=30219631" 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.ymgme.2018.09.004" target="_blank">Full Text</a>]
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Amari, S., Tsukamoto, K., Ishiguro, A., Yanagi, K., Kaname, T., Ito, Y.
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<strong>An extremely severe case of Aicardi-Goutieres syndrome 7 with a novel variant in IFIH1.</strong>
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Europ. J. Med. Genet. 63: 103646, 2020. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30965144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30965144</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30965144" 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.ejmg.2019.04.003" target="_blank">Full Text</a>]
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Asgari, S., Schlapbach, L. J., Anchisi, S., Hammer, C., Bartha, I., Junier, T., Mottet-Osman, G., Posfay-Barbe, K. M., Longchamp, D., Stocker, M., Cordey, S., Kaiser, and 9 others.
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<strong>Severe viral respiratory infections in children with IFIH1 loss-of-function mutations.</strong>
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Proc. Nat. Acad. Sci. 114: 8342-8347, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28716935/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28716935</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28716935[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=28716935" 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.1704259114" target="_blank">Full Text</a>]
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Buers, I., Rice, G. I., Crow, Y. J., Rutsch, F.
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<strong>MDA5-associated neuroinflammation and the Singleton-Merten syndrome: two faces of the same type I interferonopathy spectrum.</strong>
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J. Interferon Cytokine Res. 37: 214-219, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28475458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28475458</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28475458[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=28475458" 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/10.1089/jir.2017.0004" target="_blank">Full Text</a>]
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Bursztejn, A.-C., Briggs, T. A., del Toro Duany, Y., Anderson, B. H., O'Sullivan, J., Williams, S. G., Bodemer, C., Fraitag, S., Gebhard, F., Leheup, B., Lemelle, I., Oojageer, A., Raffo, E., Schmitt, E., Rice, G. I., Hur, S., Crow, Y. J.
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<strong>Unusual cutaneous features associated with a heterozygous gain-of-function mutation in IFIH1: overlap between Aicardi-Goutieres and Singleton-Merten syndromes.</strong>
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Brit. J. Derm. 173: 1505-1513, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26284909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26284909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26284909[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=26284909" 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/10.1111/bjd.14073" target="_blank">Full Text</a>]
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Cananzi, M., Wohler, E., Marzollo, A., Colavito, D., You, J., Jing, H., Bresolin, S., Gaio, P., Martin, R., Mescoli, C., Bade, S., Posey, J. E., and 18 others.
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<strong>Oral phenotype of Singleton-Merten syndrome: a systematic review illustrated with a case report.</strong>
|
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Front. Genet. 13: 875490, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35754802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35754802</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35754802[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=35754802" 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/10.3389/fgene.2022.875490" 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="22" class="mim-anchor"></a>
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<a id="Robinson2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Robinson, T., Kariuki, S. N., Franek, B. S., Kumabe, M., Kumar, A. A., Badaracco, M., Mikolaitis, R. A., Guerrero, G., Utset, T. O., Drevlow, B. E., Zaacks, L. S., Grober, J. S., Cohen, L. M., Kirou, K. A., Crow, M. K., Jolly, M., Niewold, T. B.
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|
<strong>Autoimmune disease risk variant of IFIH1 is associated with increased sensitivity to IFN-alpha and serologic autoimmunity in lupus patients.</strong>
|
|
J. Immun. 187: 1298-1303, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21705624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21705624</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21705624[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=21705624" 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/10.4049/jimmunol.1100857" 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="23" class="mim-anchor"></a>
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<a id="Rutsch2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rutsch, F., Kehl, H. G., Ruf, N., Vogt, J., Kleinheinz, J., Rauch, F., Hofbauer, L. C., Rehder, H., Arslan-Kirchner, M., Nurnberg, P.
|
|
<strong>Singleton-Merten syndrome: evidence of autosomal dominant inheritance in the first European family. (Abstract)</strong>
|
|
Europ. J. Hum. Genet. 13: 112-113 (P0154), 2005.
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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="24" class="mim-anchor"></a>
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<a id="Rutsch2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rutsch, F., MacDougall, M., Lu, C., Buers, I., Mamaeva, O., Nitschke, Y., Rice, G. I., Erlandsen, H., Kehl, H. G., Thiele, H., Nurnberg, P., Hohne, W., Crow, Y. J., Feigenbaum, A., Hennekam, R. C.
|
|
<strong>A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome.</strong>
|
|
Am. J. Hum. Genet. 96: 275-282, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25620204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25620204</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25620204[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=25620204" 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.ajhg.2014.12.014" 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="25" class="mim-anchor"></a>
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<a id="Soda2019" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Soda, N., Sakai, N., Kato, H., Takami, M., Fujita, T.
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<strong>Singleton-Merten syndrome-like skeletal abnormalities in mice with constitutively activated MDA5.</strong>
|
|
J. Immun. 203: 1356-1368, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31366715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31366715</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31366715" 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/10.4049/jimmunol.1900354" target="_blank">Full Text</a>]
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</p>
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</li>
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<li>
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<a id="26" class="mim-anchor"></a>
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<a id="Valverde2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Valverde, I., Rosenthal, E., Tzifa, A., Desai, P., Bell, A., Pushparajah, K., Qureshi, S., Beerbaum, P., Simpson, J.
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<strong>Singleton-Merten syndrome and impaired cardiac function.</strong>
|
|
J. Am. Coll. Cardiol. 56: 1760 only, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21070929/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21070929</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21070929" 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.jacc.2010.02.078" 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="27" class="mim-anchor"></a>
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<a id="Zaki2017" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zaki, M., Thoenes, M., Kawalia, A., Nurnberg, P., Kaiser, R., Heller, R., Bolz, H. J.
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<strong>Recurrent and prolonged infections in a child with a homozygous IFIH1 nonsense mutation.</strong>
|
|
Front. Genet. 8: 130, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29018476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29018476</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29018476[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=29018476" 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/10.3389/fgene.2017.00130" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 05/31/2023
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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">
|
|
Alan F. Scott - updated : 08/04/2022<br>Cassandra L. Kniffin - updated : 03/02/2022<br>Hilary J. Vernon - updated : 02/11/2021<br>Bao Lige - updated : 01/08/2020<br>Ada Hamosh - updated : 01/17/2019<br>Ada Hamosh - updated : 12/10/2015<br>Marla J. F. O'Neill - updated : 4/7/2015<br>Cassandra L. Kniffin - updated : 12/15/2014<br>Paul J. Converse - updated : 8/14/2014<br>Cassandra L. Kniffin - updated : 7/24/2014<br>Cassandra L. Kniffin - updated : 6/12/2014<br>Ada Hamosh - updated : 3/8/2013<br>Paul J. Converse - updated : 12/7/2011<br>George E. Tiller - updated : 11/12/2010<br>Marla J. F. O'Neill - updated : 9/24/2010<br>Marla J. F. O'Neill - updated : 2/11/2009<br>John A. Phillips, III - updated : 6/16/2008<br>Ada Hamosh - updated : 6/3/2006<br>Victor A. McKusick - updated : 5/23/2006
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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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 : 5/16/2002
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 06/01/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 05/31/2023<br>alopez : 01/04/2023<br>carol : 08/05/2022<br>carol : 08/04/2022<br>alopez : 06/15/2022<br>alopez : 03/07/2022<br>ckniffin : 03/02/2022<br>carol : 02/11/2021<br>carol : 01/09/2020<br>mgross : 01/08/2020<br>alopez : 10/10/2019<br>alopez : 01/17/2019<br>alopez : 12/10/2015<br>alopez : 12/10/2015<br>carol : 4/7/2015<br>mcolton : 4/7/2015<br>alopez : 12/18/2014<br>alopez : 12/18/2014<br>mcolton : 12/16/2014<br>ckniffin : 12/15/2014<br>mgross : 8/18/2014<br>mcolton : 8/14/2014<br>alopez : 7/30/2014<br>mcolton : 7/28/2014<br>ckniffin : 7/24/2014<br>alopez : 6/17/2014<br>mcolton : 6/16/2014<br>ckniffin : 6/12/2014<br>ckniffin : 6/12/2014<br>alopez : 3/11/2013<br>terry : 3/8/2013<br>mgross : 1/19/2012<br>terry : 12/7/2011<br>wwang : 11/19/2010<br>terry : 11/12/2010<br>wwang : 9/24/2010<br>terry : 9/24/2010<br>alopez : 8/21/2009<br>terry : 8/14/2009<br>wwang : 2/11/2009<br>terry : 2/11/2009<br>carol : 6/16/2008<br>terry : 5/15/2007<br>alopez : 6/3/2006<br>alopez : 6/1/2006<br>terry : 5/23/2006<br>mgross : 5/16/2002
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 606951
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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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INTERFERON-INDUCED HELICASE C DOMAIN-CONTAINING PROTEIN 1; IFIH1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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MELANOMA DIFFERENTIATION-ASSOCIATED GENE 5; MDA5
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: IFIH1</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
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Cytogenetic location: 2q24.2
|
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|
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Genomic coordinates <span class="small">(GRCh38)</span> : 2:162,267,074-162,318,684 </span>
|
|
</em>
|
|
</strong>
|
|
<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>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
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">
|
|
2q24.2
|
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</span>
|
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</td>
|
|
|
|
|
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<td>
|
|
<span class="mim-font">
|
|
Aicardi-Goutieres syndrome 7
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
615846
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Immunodeficiency 95
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
619773
|
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Singleton-Merten syndrome 1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
182250
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
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|
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|
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</tbody>
|
|
</table>
|
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</div>
|
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</div>
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<span class="mim-font">
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>The IFIH1 gene encodes a cytoplasmic receptor that senses dsRNA viral products to activate type I interferon signaling through the MAVS (609676) adaptor molecule. This can inhibit virus replication and modulate cellular immune responses. IFIH1 may also help recognize and limit the replication of ssRNA viruses (summary by Rice et al., 2014 and Lamborn et al., 2017). </p>
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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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<p>By screening a melanoma differentiation-subtracted library and a placenta cDNA library, followed by 5-prime RACE, Kang et al. (2002) isolated a full-length cDNA encoding IFIH1, which they called MDA5. The deduced 1,025-amino acid protein contains an N-terminal CARD motif and a C-terminal DExH/D RNA helicase domain closely related to that of RIGI (DDX58; 609631). SDS-PAGE and Western blot analysis showed expression of a 120-kD protein. Northern blot analysis revealed that treatment of melanoma cells or skin fibroblasts with beta-interferon (IFNB; 147640) enhanced MDA5 expression 3-fold more than did treatment with IFNA (147660), IFNG (147570), or tumor necrosis factor (TNF; 191160). Other differentiation reagents had little or no effect. Expression of MDA5 was further upregulated in the presence of mezerein (MEZ). In tissues, expression of MDA5 was low overall, with highest levels in placenta, pancreas, and spleen, and undetectable levels in brain, lung, and testis. Confocal microscopy demonstrated cytoplasmic expression corresponding with the absence of a nuclear localization signal in the primary amino acid sequence. Ectopic expression of MDA5 in melanoma cells resulted in reduced colony formation, suggesting an interaction of the CARD and apoptotic signal molecules. Functional analysis indicated that MDA5 is an RNA-dependent ATPase. </p><p>By fluorescence immunohistochemistry, Rutsch et al. (2015) detected MDA5 in human cardiac myocytes, epidermis, and cartilage chondrocytes. Analysis of mouse mandibles demonstrated localization of Mda5 in ameloblasts, odontoblasts, and the periodontal ligament, as well as in active osteoblasts at the surface of alveolar bone. </p>
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<strong>Gene Structure</strong>
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<p>Kang et al. (2004) determined that the IFIH1 gene contains 16 exons. </p>
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<strong>Mapping</strong>
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<p>By radiation hybrid and genomic sequence analyses, Kang et al. (2004) mapped the IFIH1 gene to chromosome 2q24. </p>
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<strong>Gene Function</strong>
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<p>Using Northern blot analysis, Kang et al. (2004) showed that human MDA5 was a general type I IFN-inducible gene with rapid temporal induction kinetics and limited basal expression in normal tissue. The JAK (see 147795)/STAT (see 600555) signaling pathway was directly involved in IFN-induced MDA5 expression. Overexpression of MDA5 induced apoptotic cell death in HO-1 melanoma cells. Mutation analysis showed that the CARD and ATPase domains of MDA5 were involved in cellular growth and survival. </p><p>Colli et al. (2010) evaluated whether modulation of MDA5 and PTPN2 (176887), 2 candidate genes for type 1 diabetes, affects beta-cell responses to double-stranded RNA (dsRNA), a by-product of viral replication. INS-1E cells and primary fluorescence-activated cell sorting-purified rat beta-cells were transfected with small interference RNAs (siRNAs) targeting MDA5 or PTPN2 and subsequently exposed to intracellular synthetic dsRNA polyinosinic-polycytidylic acid (PIC). PIC increased MDA5 and PTPN2 mRNA expression, which was inhibited by the specific siRNAs. PIC triggered apoptosis in INS-1E and primary beta-cells and this was augmented by PTPN2 knockdown, although inhibition of MDA5 did not modify PIC-induced apoptosis. In contrast, MDA5 silencing decreased PIC-induced cytokine and chemokine expression, although inhibition of PTPN2 induced minor or no changes in these inflammatory mediators. Colli et al. (2010) concluded that changes in MDA5 and PTPN2 expression modify beta-cell responses to dsRNA. MDA5 regulates inflammatory signals, whereas PTPN2 may function as a defense mechanism against proapoptotic signals generated by dsRNA. </p><p>To determine the specific of RNA editing by ADAR1 (146920), Liddicoat et al. (2015) generated mice with an editing-deficient knockin mutation, Adar1(E861A). Adar1(E861A/E861A) embryos died at approximately embryonic day 13.5, with activated interferon (see 147660) and dsRNA-sensing pathways. Genomewide analysis of the in vivo substrates of ADAR1 identified clustered hyperediting within long dsRNA stem loops within 3-prime untranslated regions of endogenous transcripts. Concurrent deletion of the cytosolic sensor of dsRNA MDA5 rescued embryonic death and other phenotypes of Adar1(E861A/E861A). Liddicoat et al. (2015) concluded that adenosine-to-inosine editing of endogenous dsRNA is the essential function of ADAR1, preventing the activation of the cytosolic dsRNA response by endogenous transcripts. </p>
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<strong>Biochemical Features</strong>
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<p><strong><em>Crystal Structure</em></strong></p><p>
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Motz et al. (2013) determined the crystal structure of the MDA5 ATP-hydrolysis domain in complex with the viral inhibitor V protein. The V protein unfolded the ATP-hydrolysis domain of MDA5 via a beta-hairpin motif and recognized a structural motif of MDA5 that is normally buried in the conserved helicase fold. This leads to disruption of the MDA5 ATP-hydrolysis site and prevention of RNA-bound MDA5 filament formation. Motz et al. (2013) explained why V proteins inactivate MDA5, but not RIGI (609631), and mutating only 2 amino acids in RIGI induces robust V protein binding. </p>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Singleton-Merten Syndrome 1</em></strong></p><p>
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In affected individuals from 3 unrelated families with early and extreme aortic and valvular calcification, dental anomalies, osteopenia, and acroosteolysis (SGMRT1; 182250), Rutsch et al. (2015) performed whole-exome sequencing and identified heterozygosity for a missense mutation in the IFIH1 gene (R822Q; 606951.0009) that segregated with disease in each family. Functional analysis demonstrated that R822Q is a gain-of-function substitution that triggers production of type 1 interferon, resulting in a heightened inflammatory state. </p><p>In a French father with Singleton-Merten syndrome and his 2 affected sons with a variable neurologic presentation, Bursztejn et al. (2015) identified heterozygosity for a missense mutation in the IFIH1 gene (A489T; 606951.0015). </p><p>In 5 affected individuals from 2 unrelated families with Singleton-Merten syndrome, de Carvalho et al. (2017) sequenced the IFIH1 gene and identified heterozygosity for 2 different missense mutations at the same residue: a T331I substitution (606951.0016) in family 1938, and a T331R substitution (606951.0017) in family 1972. Both variants resulted in markedly increased levels of IFN signaling. </p><p>In a 10-year-old boy with Singleton-Merten syndrome, Riou et al. (2022) identified heterozygosity for the recurrent R822Q mutation in the IFIH1 gene. </p><p><strong><em>Aicardi-Goutieres Syndrome 7</em></strong></p><p>
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In 8 probands with Aicardi-Goutieres syndrome 7 (AGS7; 615846), Rice et al. (2014) identified 6 different heterozygous mutations in the IFIH1 gene (606951.0001-606951.0006). The first 3 mutations were found by whole-exome sequencing. The mutations in 5 probands occurred de novo, whereas in 2 they were paternally transmitted; for 1 proband parental DNA was unavailable. In 1 family, 2 mutation carriers remained clinically unaffected as adults. In vitro functional expression assays in HEK293T cells showed that the mutations caused marked induction of interferon signaling in response to short 162-bp double-stranded RNA (dsRNA), whereas control cells did not. The mutations also conferred 4- to 10-fold higher levels of basal signaling activity even in the absence of exogenous ligand. The mutated residues were located on the surface of the RNA-binding and ATP-binding sites in conserved helicase domains, but ATP hydrolysis activity of the mutants was comparable to wildtype. Structural modeling and biochemical studies indicated that the mutations enhance the stability of the activated IFIH1 filament by increasing affinity for dsRNA. These findings were consistent with a gain of function, resulting in increased interferon signaling. The findings also suggested the presence of an undefined endogenous dsRNA capable of stimulating mutant receptors. </p><p>In 3 unrelated Japanese patients with AGS7, Oda et al. (2014) identified 3 different de novo heterozygous missense mutations in the IFIH1 gene (606951.0002, 606951.0007, and 606951.0008). The mutations were found by trio-based whole-exome sequencing. Peripheral blood cells from the patients showed a type 1 interferon signature, and expression of each of the mutations in a human hepatoma cell line resulted in increased activation of the IFNB1 (147640) promoter compared to wildtype, consistent with increased type I interferon production. In vitro studies showed that the mutant IFIH1 proteins lacked ligand-specific responsiveness. </p><p>In a 6-year-old boy with bilateral spasticity, developmental delay, and basal ganglia calcification, Buers et al. (2017) identified heterozygosity for the recurrent R822Q mutation in the IFIH1 gene (606951.0009), previously reported in patients with Singleton-Merten syndrome. The authors concluded that both diseases are part of an 'interferonopathy grouping,' and that the R822Q mutation can cause a spectrum of disease, including neurologic involvement. </p><p>In a female infant with AGS7, Amari et al. (2020) identified a de novo heterozygous mutation in the IFIH1 gene (E813D; 606951.0010). The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. </p><p><strong><em>Immunodeficiency 95</em></strong></p><p>
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In a 5-year-old girl from Burma with immunodeficiency-95 (IMD95; 619773), Lamborn et al. (2017), identified a homozygous missense mutation in the IFIH1 gene (K365E; 606951.0011). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in the unaffected parents and brother. In vitro functional expression studies of patient cells and cells transfected with the mutation showed that the K365E mutant had minimal IFNB1 (147640) and NFKB (see 164011) promoter activity after stimulation with poly(I:C) compared to wildtype. Cotransfection of the mutant with wildtype showed no dominant-negative effects; the findings were consistent with a loss of function. Cells with the mutation and cells with silencing of the IFIH1 gene demonstrated increased replication of human rhinovirus (HRV) and impaired interferon signaling compared to controls. However, these cells did not show increased viral replication of influenza or RSV. Transduction with wildtype, but not mutant, IFIH1 improved control of HRV replication. The findings were consistent with impaired viral recognition and antiviral responses specific for HRV. </p><p>In a 6-year-old girl, born of consanguineous Egyptian parents, with IMD95, Zaki et al. (2017) identified a homozygous nonsense mutation in the IFIH1 gene (K889X; 606951.0012). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in the unaffected parents and sib. Western blot analysis of patient fibroblasts showed significantly decreased IFIH1 protein levels compared to controls, suggesting that the mutant transcript undergoes nonsense-mediated mRNA decay and results in a loss of function. In addition to IMD95, manifest as recurrent severe viral respiratory infections and persistent EBV infection, the patient also had a severe neurodevelopmental disorder with seizures and microcephaly associated with a homozygous missense mutation in the PHGDH gene (V425M; 606879.0002). </p><p>In 3-year-old girl (patient 1), born of consanguineous Moroccan parents, with IMD95, Cananzi et al. (2021) identified a homozygous frameshift mutation in the IFIH1 gene (606951.0013). It was predicted to result in nonsense-mediated mRNA decay or produce a truncated protein lacking important functional domains. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each unaffected parent. In vitro functional studies using a luciferase reporter assay showed that mutant IFIH1 failed to activate the IFNB1 (147640) promoter following stimulation, consistent with a loss-of-function effect. In addition to recurrent and severe infections, including with CMV, the patient also had very early-onset inflammatory bowel disease (VEOIBD) in the first weeks of life. </p><p>In a girl (PRI_022) with IMD95, Asgari et al. (2017) identified a homozygous splice site mutation in the IFIH1 gene (606951.0014). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present at a low frequency in the gnomAD database (0.64%), including 7 homozygotes. Western blot analysis of patient cells showed that the mutant protein was expressed upon in vitro RSV infection. In vitro functional expression studies in HEK293T cells transfected with the mutation showed that the mutant protein was unstable, failed to lead to IFNB1 (147640) production, and had no detectable ATPase activity compared to wildtype, consistent with a loss-of-function effect. There was also evidence for a dominant-negative effect on the wildtype protein. Additional in vitro studies showed that RSV and HRV replication levels were increased in cells transduced with the mutation, indicating a central role for IFIH1 in innate immune recognition of RSV and HRV and in controlling these infections. Three additional children with severe early-onset viral HRC or RSV respiratory infections were heterozygous for the splice site variant and 4 further children were heterozygous for other loss-of-function variants in the IFIH1 gene, suggesting that heterozygosity may confer susceptibility to the disease. However, carrier parents were unaffected. The patients were part of a cohort of 120 children with severe manifestations of common viral respiratory infections who underwent exome sequencing. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between variation in the IFIH1 gene and type 1 diabetes, see IDDM19 (610155).</p><p>For discussion of a possible association between variation in the IFIH1 gene and Graves disease, see 275000.</p><p>For discussion of a possible association between variation in the IFIH1 gene and selective immunoglobulin A deficiency, see IGAD1 (137100).</p><p>Robinson et al. (2011) studied the impact of the IFIH1 946A-T SNP (rs1990760) in 563 American patients of various ethnicities with systemic lupus erythematosus (SLE; 152700). They found that the T allele of rs1990760 was associated with anti-double-stranded DNA (dsDNA) antibodies in all groups, and that, among those with anti-dsDNA antibodies, the T allele was associated with lower serum IFNA. The T allele was also associated with increased IFN-induced gene expression in peripheral blood mononuclear cells in response to serum IFNA in anti-dsDNA antibody-positive patients, independent of the STAT4 (600558) genotype. Robinson et al. (2011) suggested that the T allele of rs1990760 may have a role in SLE pathogenesis. </p><p>Gorman et al. (2017) noted that the 946A-T variant has been associated with multiple autoimmune diseases. The authors found that peripheral blood mononuclear cells (PBMCs) from healthy donors with the 946A-T variant had increased interferon production in response to the ligand poly(I:C). Homozygotes also had significantly increased expression of interferon-stimulated genes. The authors showed that mice with a knockin 946A-T variant had increased basal interferon expression and better survived a viral challenge but had autoimmunity-related phenotypes including increased risk of diabetes and lupus. The authors suggested that survival of the variant in human populations is likely a case of balanced selection between response to viral infection versus risks from autoimmune diseases. </p><p>In 7 unrelated patients (patients 2-8) of various ethnic origins with very early-onset inflammatory bowel disease (VEOIBD), Cananzi et al. (2021) identified heterozygous loss-of-function variants in the IFIH1 gene (see, e.g., 606951.0014). The variants, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were present at low frequencies in the gnomAD database. There were 2 nonsense, 1 frameshift, and 1 splice site variant. The variants were inherited from an unaffected parent in 6 cases, consistent with incomplete penetrance and suggesting that the variants may confer susceptibility to the disease. The patients were diagnosed with Crohn disease (4), ulcerative colitis (2), and IBD with diffuse colonic nodular lymphatic hyperplasia (1). The median age at onset was 24 months (range, 3 months to 6 years), and the patients presented with bloody, mucous, protein-losing inflammatory diarrhea and poor overall growth. Colonoscopy showed multiple linear deep ulcers separated by skip areas of normal mucosa, and histology showed ileal and colonic inflammation with villous atrophy, crypt distortion, mucinous hyperplasia of colonocytes, and Paneth cell metaplasia. Laboratory studies showed elevated inflammatory markers such as ESR and CRP, anemia, and hypoalbuminemia. Cananzi et al. (2021) proposed that compromised microbacterial sensing due to the variants impairs IFIH1 activation and interferon production, leading to impairment of innate immune defenses and chronic intestinal inflammation. Additional environmental and genetic factors likely modify the risk of developing the disease. </p>
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</span>
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<h4>
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<strong>Animal Model</strong>
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<span class="mim-text-font">
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<p>Using mice deficient in MDA5, Kato et al. (2006) showed that MDA5 and RIGI (609631) recognize different types of double-stranded RNAs: MDA5 recognizes PIC and RIGI detects in vitro transcribed double-stranded RNAs. RNA viruses are also differentially recognized by RIGI and MDA5. Kato et al. (2006) found that RIGI is essential for the production of interferons in response to RNA viruses including paramyxoviruses, influenza virus, and Japanese encephalitis virus, whereas MDA5 is critical for picornavirus detection. Furthermore, Rig1-null and Mda5-null mice are highly susceptible to infection with these respective RNA viruses compared to control mice. Kato et al. (2006) concluded that, taken together, their data show that RIGI and MDA5 distinguish different RNA viruses and are critical for host antiviral responses. </p><p>Using chemical mutagenesis, Funabiki et al. (2014) generated mice with a mutation in exon 13 of Mda5, resulting in a gly821-to-ser (G821S) substitution. These mice spontaneously developed lupus-like nephritis and systemic autoimmune symptoms without viral infection. Mutant mice that also lacked Mavs failed to develop nephritis, and mutant mice that also lacked Ifnar1 (107450) had a partially ameliorated nephritis. The G821S mutant could activate signaling in the absence of its ligand, but it was defective for ligand- and virus-induced signaling, suggesting a possible conformational change in Mda5. Funabiki et al. (2014) concluded that dysregulation of the innate immune sensor MDA5 causes autoimmune disorders. </p><p>Soda et al. (2019) found that mice with the constitutively active Mda5 G821S mutation exhibited growth retardation and decreased bone mineralization due to attenuated bone formation from osteoblasts and bone resorption by osteoclasts. The Mda5 G821S mutation did not intrinsically affect osteoclast function, but osteoclast differentiation from osteoclast precursor cells was extrinsically affected by exogenous type I Ifn that was induced by Mda5/Mavs signaling and played a central role in abnormal bone metabolism. </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>17 Selected Examples):</strong>
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</span>
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<h4>
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<span class="mim-font">
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<strong>.0001 AICARDI-GOUTIERES SYNDROME 7</strong>
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IFIH1, ARG720GLN
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<br />
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SNP: rs587777445,
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ClinVar: RCV000125470, RCV001849907, RCV004558317
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<span class="mim-text-font">
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<p>In 2 unrelated patients of European descent with Aicardi-Goutieres syndrome-7 (AGS7; 615846), Rice et al. (2014) identified a de novo heterozygous c.2159G-A transition in exon 11 of the IFIH1 gene, resulting in an arg720-to-gln (R720Q) substitution at a highly conserved residue in the core helicase-2 domain. The mutation in the first patient was found by whole-exome sequencing and confirmed by Sanger sequencing. It was not present in the Exome Sequencing Project database or in over 300 in-house control exomes. In vitro functional expression assays in HEK293T cells showed that the mutation caused marked induction of interferon signaling in response to short 162-bp double-stranded RNA (dsRNA) compared to controls. The mutation conferred 4- to 10-fold higher levels of basal signaling activity even in the absence of exogenous ligand. These findings were consistent with a gain of function, resulting in increased interferon signaling. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 AICARDI-GOUTIERES SYNDROME 7</strong>
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</span>
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<span class="mim-text-font">
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IFIH1, ARG779HIS
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<br />
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SNP: rs587777446,
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gnomAD: rs587777446,
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ClinVar: RCV000125471, RCV000412770, RCV000626957, RCV000763454, RCV001770100, RCV003989322, RCV004745206
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<span class="mim-text-font">
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<p>In 2 unrelated patients with Aicardi-Goutieres syndrome-7 (AGS7; 615846), Rice et al. (2014) identified a heterozygous c.2336G-A transition in exon 12 of the IFIH1 gene, resulting in an arg779-to-his (R779H) substitution at a highly conserved residue in the core helicase-2 domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the Exome Sequencing Project database or in over 300 in-house control exomes. The mutation occurred de novo in 1 patient. In the second family, the clinically asymptomatic father and paternal grandmother also carried the mutation, suggesting incomplete penetrance. However, all 3 mutation carriers in this family had a robust interferon signature. Rice et al. (2014) suggested that the phenotypic variability in this family may have resulted from additional environmental or genetic factors. In vitro functional expression assays in HEK293T cells showed that the mutation caused marked induction of interferon signaling in response to short 162-bp double-stranded RNA (dsRNA) compared to controls. The mutation conferred 4- to 10-fold higher levels of basal signaling activity even in the absence of exogenous ligand. These findings were consistent with a gain of function, resulting in increased interferon signaling. </p><p>Oda et al. (2014) identified a de novo heterozygous R779H mutation in a Japanese girl with AGS7. The mutation was found by trio-based whole-exome sequencing and confirmed by Sanger sequencing. </p>
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<h4>
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<span class="mim-font">
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<strong>.0003 AICARDI-GOUTIERES SYNDROME 7</strong>
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</h4>
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<span class="mim-text-font">
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IFIH1, ARG337GLY
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|
<br />
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|
SNP: rs587777447,
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|
|
ClinVar: RCV000125472
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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 European American patient with Aicardi-Goutieres syndrome-7 (AGS7; 615846), Rice et al. (2014) identified a de novo heterozygous c.1009A-G transition in exon 5 of the IFIH1 gene, resulting in an arg337-to-gly (R337G) substitution at a highly conserved residue in the core helicase-1 domain. The mutation was not found in the Exome Sequencing Project database or in over 300 in-house control exomes. In vitro functional expression assays in HEK293T cells showed that the mutation caused marked induction of interferon signaling in response to short 162-bp double-stranded RNA (dsRNA) compared to controls. The mutation conferred 4- to 10-fold higher levels of basal signaling activity even in the absence of exogenous ligand. These findings were consistent with a gain of function, resulting in increased interferon signaling. </p><p>Adang et al. (2018) identified this mutation in a 16-year-old boy with AGS7 who died from cardiopulmonary arrest. Pulmonary hypertension was identified at autopsy. The mutation was shown to have occurred de novo. </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 AICARDI-GOUTIERES SYNDROME 7</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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IFIH1, ARG779CYS
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<br />
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|
SNP: rs587777448,
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|
ClinVar: RCV000125473, RCV000255113, RCV001382400
|
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|
</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient of British descent with Aicardi-Goutieres syndrome-7 (AGS7; 615846), Rice et al. (2014) identified a heterozygous c.2335C-T transition in exon 12 of the IFIH1 gene, resulting in an arg779-to-cys (R779C) substitution at a highly conserved residue in the core helicase-2 domain. The mutation was not found in the Exome Sequencing Project database or in over 300 in-house control exomes. In vitro functional expression assays in HEK293T cells showed that the mutation caused marked induction of interferon signaling in response to short 162-bp double-stranded RNA (dsRNA) compared to controls. The mutation conferred 4- to 10-fold higher levels of basal signaling activity even in the absence of exogenous ligand. These findings were consistent with a gain of function, resulting in increased interferon 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>
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<h4>
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<span class="mim-font">
|
|
<strong>.0005 AICARDI-GOUTIERES SYNDROME 7</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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IFIH1, GLY495ARG
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<br />
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SNP: rs672601336,
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ClinVar: RCV000125474, RCV004812301
|
|
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|
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</span>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a British father and daughter (F524) with Aicardi-Goutieres syndrome-7 (AGS7; 615846), Rice et al. (2014) identified a heterozygous c.1483G-A transition in exon 7 of the IFIH1 gene, resulting in a gly495-to-arg (G495R) substitution at a conserved residue in the core helicase-1 domain. The mutation was not found in the Exome Sequencing Project database or in over 300 in-house control exomes. The mutation occurred de novo in the father. In vitro functional expression assays in HEK293T cells showed that the mutation caused marked induction of interferon signaling in response to short 162-bp double-stranded RNA (dsRNA) compared to controls. The mutation conferred 4- to 10-fold higher levels of basal signaling activity even in the absence of exogenous ligand. These findings were consistent with a gain of function, resulting in increased interferon signaling. The patients had a unique phenotype characterized mainly by early-onset spastic paraparesis; the daughter also developed had a multisystem inflammatory process with brain imaging abnormalities. The British father was also reported by Crow et al. (2014). He had onset of motor symptoms around 2 years of age when he developed toe-walking and frequent falls after normal early development. He was diagnosed with cerebral palsy, but the disorder was slowly progressive. At age 33 years, he showed lower limb spasticity without upper limb involvement. Brain imaging and cognition were normal at the age of 29 years. Laboratory studies showed persistently increased interferon. Crow et al. (2014) emphasized the phenotypic variability associated with AGS, noting that neurologic dysfunction is not always marked in this disorder. </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>.0006 AICARDI-GOUTIERES SYNDROME 7</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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IFIH1, ASP393VAL
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<br />
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|
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SNP: rs587777449,
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|
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gnomAD: rs587777449,
|
|
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|
|
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ClinVar: RCV000125475
|
|
|
|
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In an Italian patient with Aicardi-Goutieres syndrome-7 (AGS7; 615846), Rice et al. (2014) identified a de novo heterozygous c.1178A-T transversion in exon 6 of the IFIH1 gene, resulting in an asp393-to-val (D393V) substitution at a highly conserved residue in the core helicase-1 domain. The mutation was not found in the Exome Sequencing Project database or in over 300 in-house control exomes. In vitro functional expression assays in HEK293T cells showed that the mutation caused marked induction of interferon signaling in response to short 162-bp double-stranded RNA (dsRNA) compared to controls. The mutation conferred 4- to 10-fold higher levels of basal signaling activity even in the absence of exogenous ligand. These findings were consistent with a gain of function, resulting in increased interferon signaling. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 AICARDI-GOUTIERES SYNDROME 7</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
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|
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|
IFIH1, ALA452THR
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|
<br />
|
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|
|
SNP: rs587777575,
|
|
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|
|
|
ClinVar: RCV000128858
|
|
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|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese boy with Aicardi-Goutieres syndrome-7 (AGS7; 615846), Oda et al. (2014) identified a de novo heterozygous c.1354G-A transition in the IFIH1 gene, resulting in an ala452-to-thr (A452T) substitution at a conserved residue in the helicase domain. The mutation, which was found by trio-based exome sequencing, was filtered against the dbSNP (build 137) database and was not present in an in-house exome database of 312 Japanese individuals. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 AICARDI-GOUTIERES SYNDROME 7</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
IFIH1, LEU372PHE
|
|
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|
|
|
<br />
|
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|
|
SNP: rs587777576,
|
|
|
|
|
|
|
|
ClinVar: RCV000128859
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese boy with Aicardi-Goutieres syndrome-7 (AGS7; 615846), Oda et al. (2014) identified a de novo heterozygous c.1114C-T transition in the IFIH1 gene, resulting in a leu372-to-phe (L372F) substitution at a conserved residue in the helicase domain. The mutation, which was found by trio-based exome sequencing, was filtered against the dbSNP (build 137) database and was not present in an in-house exome database of 312 Japanese individuals. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
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<div>
|
|
<br />
|
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</div>
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|
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</div>
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<div>
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 SINGLETON-MERTEN SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
AICARDI-GOUTIERES SYNDROME 7, INCLUDED
|
|
</span>
|
|
</div>
|
|
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|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
IFIH1, ARG822GLN ({dbSNP rs376048533})
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|
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|
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<br />
|
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|
|
SNP: rs376048533,
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|
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|
|
gnomAD: rs376048533,
|
|
|
|
|
|
ClinVar: RCV000169754, RCV000436896, RCV000789041, RCV000822311, RCV004745248
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Singleton-Merten Syndrome 1</em></strong></p><p>
|
|
In affected individuals from 3 unrelated families with early and extreme aortic and valvular calcification, dental anomalies, osteopenia, and acroosteolysis (SGMRT1; 182250), previously reported by Feigenbaum et al. (1988), Rutsch et al. (2005), and Valverde et al. (2010), respectively, Rutsch et al. (2015) performed whole-exome sequencing and identified heterozygosity for a c.2465G-A transition in the IFIH1 gene, resulting in an arg822-to-gln (R822Q) substitution at a highly conserved residue in 1 of 2 core helicase domains. The mutation, which segregated with disease in each family, was not found in any unaffected family members; analysis of 17 additional family members from the largest family showed that all but 1 individual with dental anomalies carried the mutation, and 1 individual with only psoriasis carried the mutation, whereas 3 others with only psoriasis did not. The authors noted that the IFIH1 c.2465G-A variant has been reported as a SNP (rs376048533) in 1 individual with 'cardiac and pulmonary phenotypes' from among 6,517 individuals in the NHLBI Exome Variant Server database, and is listed in the Exome Aggregation Consortium Browser with an allele frequency of 0.00002481. In vitro functional analysis revealed that the R822Q mutant enhanced MDA5 function in interferon-beta (IFNB1; 147640) induction, and interferon signature genes were upregulated in patient blood and dental cells. Rutsch et al. (2015) concluded that R822Q is a gain-of-function substitution that causes Singleton-Merten syndrome through dysregulation of the human innate immune response. </p><p>In a 10-year-old boy with Singleton-Merten syndrome, Riou et al. (2022) identified heterozygosity for the recurrent R822Q mutation (c.2465G-A, NM_022168.4) in the IFIH1 gene. The mutation arose de novo. </p><p><strong><em>Aicardi-Goutieres Syndrome 7</em></strong></p><p>
|
|
In a 6-year-old boy with bilateral spasticity, developmental delay, and basal ganglia calcification (AGS7; 615846), Buers et al. (2017) identified heterozygosity for the R822Q mutation in the IFIH1 gene. The mutation was not present in parental DNA and was considered to have arisen de novo. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 AICARDI-GOUTIERES SYNDROME 7</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
IFIH1, GLU813ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1559810905,
|
|
|
|
|
|
|
|
ClinVar: RCV000761569
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a female infant with Aicardi-Goutieres syndrome-7 (AGS7; 615846), Amari et al. (2020) identified a de novo heterozygous c.2439A-T transversion (c.2439A-T, NM_022168) in exon 12 of the IFIH1 gene, resulting in a glu813-to-asp (E813D) substitution in the HEL2 domain. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. The mutation was not present in the gnomAD database or in an in-house database. Functional studies were not performed. The patient had prenatal findings including cardiomegaly, pericardial effusion, and intracranial calcifications. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 IMMUNODEFICIENCY 95</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
IFIH1, LYS365GLU ({dbSNP rs117608083})
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs117608083,
|
|
|
|
|
|
gnomAD: rs117608083,
|
|
|
|
|
|
ClinVar: RCV001517044, RCV001843590
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 5-year-old girl from Burma with immunodeficiency-95 (IMD95; 619773), Lamborn et al. (2017), identified a homozygous c.1093A-G transition (c.1093A-G, NM_022168.3) in the IFIH1 gene, resulting in a lys365-to-glu (K365E) substitution at a conserved residue in the Hel1 domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was found at a low frequency in the ExAC database (0.06%) only in the heterozygous state and mainly in Asian populations. Both unaffected parents and an unaffected brother were heterozygous for the mutation. Patient cells showed normal protein levels, but the mutant protein was unable to bind to the poly(I:C) ligand, suggesting improper assembly and impaired downstream signaling. In vitro functional expression studies using a luciferase reporter assay demonstrated that the K365E mutant had minimal IFNB1 (147640) and NFKB (see 164011) promoter activity after stimulation with poly(I:C) compared to wildtype. Cotransfection of the mutant with wildtype showed no dominant-negative effects; the findings were consistent with a loss of function. Increased human rhinovirus (HRV) replication was observed in patient primary respiratory nasal epithelial cells compared to controls. However, these cells did not show increased viral replication of influenza or RSV. Similarly, silencing of IFIH1 in a respiratory epithelial cell line resulted in increased HRV transcripts, increased production of infectious virus, and decreased levels of IFN-regulated transcripts after HRV infection compared to controls, consistent with impaired viral recognition and antiviral responses. Transduction with wildtype, but not mutant, IFIH1 improved control of HRV replication. Similar to patient cells, silencing of IFIH1 did not increase replication of influenza or RSV in vitro. Overall, these findings indicated that IFIH1 has a nonredundant role in immunity against respiratory infections specifically caused by HRV. The patient had early-onset recurrent viral respiratory infections often requiring hospitalization. She also carried a heterozygous 4-bp deletion in the TM4SF20 gene (615404.0001) that likely explained her delays in motor and language development. Genetic analysis also identified 14 other homozygous missense mutations, 2 compound heterozygous missense mutations, and 3 de novo missense mutations, but the IFIH1 mutation was computationally predicted and functionally demonstrated to be deleterious. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 IMMUNODEFICIENCY 95</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
IFIH1, LYS889TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1252022173,
|
|
|
|
|
|
gnomAD: rs1252022173,
|
|
|
|
|
|
ClinVar: RCV001843699, RCV001869858
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 6-year-old girl, born of consanguineous Egyptian parents, with immunodeficiency-95 (IMD95; 619773), Zaki et al. (2017) identified a homozygous c.2665A-T transversion (c.2665A-T, NM_022168.2) in exon 14 of the IFIH1 gene, resulting in a lys889-to-ter (K889X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in the unaffected parents and sib. It was not present in the ExAC or 1TGP databases. Western blot analysis of patient fibroblasts showed significantly decreased IFIH1 protein levels compared to controls, suggesting that the mutant transcript undergoes nonsense-mediated mRNA decay and results in a loss of function. In addition to IMD95, manifest as recurrent severe viral respiratory infections and persistent EBV infection, the patient also had a severe neurodevelopmental disorder with seizures and microcephaly associated with a homozygous missense mutation in the PHGDH gene (V425M; 606879.0002). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 IMMUNODEFICIENCY 95</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
IFIH1, 1-BP DEL, 2016A ({dbSNP rs773033563})
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs773033563,
|
|
|
|
|
|
gnomAD: rs773033563,
|
|
|
|
|
|
ClinVar: RCV000704039, RCV000986844, RCV001091997, RCV001731900, RCV001779064, RCV001844227, RCV005021094
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3-year-old girl (patient 1), born of consanguineous Moroccan parents, with immunodeficiency-95 (IMD95; 619773), Cananzi et al. (2021) identified a homozygous 1-bp deletion (c.2016delA, NM_022168) in exon 10 of the IFIH1 gene, resulting in a frameshift and premature termination (Asp673IlefsTer5) in the Hel2i domain. It was predicted to result in nonsense-mediated mRNA decay or produce a truncated protein lacking important functional domains. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each unaffected parent. The mutation was found at a low frequency in the gnomAD database (2.99 x 10(-4)). In vitro functional studies using a luciferase reporter assay showed that mutant IFIH1 failed to activate the IFNB1 (147640) promoter following stimulation, consistent with a loss-of-function effect. In addition to recurrent and severe infections, including with CMV, the patient also had very early-onset inflammatory bowel disease (VEOIBD) in the first weeks of life. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0014 IMMUNODEFICIENCY 95</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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IFIH1, IVS14DS, G-A, +1 ({dbSNP rs35732034})
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<br />
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SNP: rs35732034,
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gnomAD: rs35732034,
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ClinVar: RCV000652102, RCV001775941, RCV001844209, RCV002499122, RCV003447548, RCV003918068
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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 16-month-old girl (PRI_022) with immunodeficiency-95 (IMD95; 619773), Asgari et al. (2017) identified a homozygous splice site mutation in the IFIH1 gene, resulting in a splicing defect, the skipping of exon 14, a frameshift, and premature termination (Ile872Ter). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present at a low frequency in the gnomAD database (0.64%). The mutation was inherited from her unaffected parents. In vitro functional expression studies in HEK293T cells transfected with the mutation showed that the mutant protein was unstable, failed to lead to IFNB1 (147640) production, and had no detectable ATPase activity compared to wildtype, consistent with a loss-of-function effect. There was also evidence for a dominant-negative effect on the wildtype protein. Additional in vitro studies showed that RSV and HRV replication levels were increased in cells transduced with the mutation, indicating a central role for IFIH1 in innate immune recognition of RSV and HRV and in controlling these infections. The patient presented with early-onset respiratory failure associated with RSV infection. Three additional children with severe early-onset viral HRC or RSV respiratory infections were heterozygous for the splice site variant; however, 2 patient inherited the variant from an unaffected parent. These findings suggested that heterozygosity for loss-of-function IFIH1 variants may confer susceptibility to the disease. </p><p><strong><em>Association Pending Confirmation</em></strong></p><p>
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In 2 unrelated patients (P3 and P7) with very early-onset inflammatory bowel disease (VEOIBD), Cananzi et al. (2021) identified the same intron 14 splice site mutation (c.2807+1G-A, NM_022168) in heterozygous state. This variant, which was identified by whole-exome sequencing, was inherited from an unaffected parent in both families, suggesting incomplete penetrance. In vitro functional expression studies using a luciferase reporter assay showed that the variant IFIH1 failed to activate the IFNB1 promoter following stimulation, consistent with a loss-of-function effect. Both patients with VEOIBD and the c.2807+1G-A mutation also carried an inherited T702I missense variant (one in trans, the other in cis) in the IFIH1 gene that had no functional effect. </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>.0015 SINGLETON-MERTEN SYNDROME 1</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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IFIH1, ALA489THR
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<br />
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SNP: rs1576226604,
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ClinVar: RCV001003356, RCV003234569
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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 French father and 2 sons with Singleton-Merten syndrome (SGMRT1; 182250), Bursztejn et al. (2015) identified heterozygosity for a c.1465G-A transition in the IFIH1 gene, resulting in an ala489-to-thr (A489T) substitution at a highly conserved residue within the core helicase Hel1 domain. The mutation, which was not found in the ExAC database, was also not present in the paternal grandparents, indicating a de novo origin or gonadal mosaicism. The A489T mutant showed impaired ATP hydrolysis activity compared to wildtype IFIH1, and the mutant protein-RNA complex showed increased stability in the presence of ATP compared to wildtype. Analysis of transfected HEK293T cells revealed that basal levels of interferon signaling were markedly increased in the absence of exogenous RNA with the A489T mutant. In addition, mutant IFIH1 displayed marked interferon induction following stimulation with either long or short double-stranded RNA. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0016 SINGLETON-MERTEN SYNDROME 1</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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IFIH1, THR331ILE
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<br />
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SNP: rs1576229572,
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ClinVar: RCV001003351, RCV003234568
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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 an 18-year-old girl, her mother, and maternal aunt (family 1938) with Singleton-Merten syndrome (SGMRT1; 182250), de Carvalho et al. (2017) identified heterozygosity for a c.992C-T transition (c.992C-T, NM_022168) in the IFIH1 gene, resulting in a thr331-to-ile (T331I) substitution at a highly conserved residue within the Hel1 core helicase domain. Familial segregation was not reported. The variant was not found in the ExAC database. Studies in HEK293T cells showed that basal levels of IFN signaling were markedly increased with the T331I mutant in the absence of endogenous dsRNA ligand, consistent with constitutive activation of MDA5. </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>.0017 SINGLETON-MERTEN SYNDROME 1</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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IFIH1, THR331ARG
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<br />
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SNP: rs1576229572,
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ClinVar: RCV001003350, RCV003234567
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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 a 9-year-old girl and her affected father (family 1972) with Singleton-Merten syndrome (SGMRT1; 182250), de Carvalho et al. (2017) identified heterozygosity for a c.992C-G transition (c.992C-G, NM_022168) in the IFIH1 gene, resulting in a thr331-to-arg (T331R) substitution at a highly conserved residue within the Hel1 core helicase domain. Familial segregation was not reported. The variant was not found in the ExAC database. Studies in HEK293T cells showed that basal levels of IFN signaling were markedly increased with the T331R mutant in the absence of endogenous dsRNA ligand, consistent with constitutive activation of MDA5. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
|
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Adang, L. A., Frank, D. B., Gilani, A., Takanohashi, A., Ulrick, N., Collins, A., Cross, Z., Galambos, C., Helman, G., Kanaan, U., Keller, S., Simon, D., Sherbini, O., Hanna, B. D., Vanderver, A. L.
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<strong>Aicardi goutieres syndrome is associated with pulmonary hypertension.</strong>
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Molec. Genet. Metab. 125: 351-358, 2018.
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[Full Text: https://doi.org/10.1016/j.ymgme.2018.09.004]
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<p class="mim-text-font">
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Amari, S., Tsukamoto, K., Ishiguro, A., Yanagi, K., Kaname, T., Ito, Y.
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<strong>An extremely severe case of Aicardi-Goutieres syndrome 7 with a novel variant in IFIH1.</strong>
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Europ. J. Med. Genet. 63: 103646, 2020. Note: Electronic Article.
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<p class="mim-text-font">
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Asgari, S., Schlapbach, L. J., Anchisi, S., Hammer, C., Bartha, I., Junier, T., Mottet-Osman, G., Posfay-Barbe, K. M., Longchamp, D., Stocker, M., Cordey, S., Kaiser, and 9 others.
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<strong>Severe viral respiratory infections in children with IFIH1 loss-of-function mutations.</strong>
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Proc. Nat. Acad. Sci. 114: 8342-8347, 2017.
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<p class="mim-text-font">
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Buers, I., Rice, G. I., Crow, Y. J., Rutsch, F.
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<strong>MDA5-associated neuroinflammation and the Singleton-Merten syndrome: two faces of the same type I interferonopathy spectrum.</strong>
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J. Interferon Cytokine Res. 37: 214-219, 2017.
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[PubMed: 28475458]
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Bursztejn, A.-C., Briggs, T. A., del Toro Duany, Y., Anderson, B. H., O'Sullivan, J., Williams, S. G., Bodemer, C., Fraitag, S., Gebhard, F., Leheup, B., Lemelle, I., Oojageer, A., Raffo, E., Schmitt, E., Rice, G. I., Hur, S., Crow, Y. J.
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<strong>Unusual cutaneous features associated with a heterozygous gain-of-function mutation in IFIH1: overlap between Aicardi-Goutieres and Singleton-Merten syndromes.</strong>
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Brit. J. Derm. 173: 1505-1513, 2015.
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[Full Text: https://doi.org/10.1111/bjd.14073]
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Cananzi, M., Wohler, E., Marzollo, A., Colavito, D., You, J., Jing, H., Bresolin, S., Gaio, P., Martin, R., Mescoli, C., Bade, S., Posey, J. E., and 18 others.
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<strong>IFIH1 loss-of-function variants contribute to very early-onset inflammatory bowel disease.</strong>
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Hum. Genet. 140: 1299-1312, 2021.
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[PubMed: 34185153]
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[Full Text: https://doi.org/10.1007/s00439-021-02300-4]
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Colli, M. L., Moore, F., Gurzov, E. N., Ortis, F., Eizirik, D. L.
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<strong>MDA5 and PTPN2, two candidate genes for type 1 diabetes, modify pancreatic beta-cell responses to the viral by-product double-stranded RNA.</strong>
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Hum. Molec. Genet. 19: 135-146, 2010.
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Crow, Y. J., Zaki, M. S., Abdel-Hamid, M. S., Abdel-Salam, G., Boespflug-Tanguy, O., Cordeiro, N. J. V., Gleeson, J. G., Gowrinathan, N. R., Laugel, V., Renaldo, F., Rodriguez, D., Livingston, J. H., Rice, G. I.
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<strong>Mutations in ADAR1, IFIH1, and RNASEH2B presenting as spastic paraplegia.</strong>
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Neuropediatrics 45: 386-391, 2014.
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[PubMed: 25243380]
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<p class="mim-text-font">
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de Carvalho, L. M., Ngoumou, G., Park, J. W., Ehmke, N., Deigendesch, N., Kitabayashi, N., Melki, I., Souza, F. F. L., Tzschach, A., Nogueira-Barbosa, M. H., Ferriani, V., Louzada-Junior, P., Marques, W., Lourenco, C. M., Horn, D., Kallinich, T., Stenzel, W., Hur, S., Rice, G. I., Crow, Y. J.
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<strong>Musculoskeletal disease in MDA5-related type I interferonopathy: a mendelian mimic of Jaccoud's arthropathy.</strong>
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Am. J. Hum. Genet. 43: A48 only, 1988.
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Funabiki, M., Kato, H., Miyachi, Y., Toki, H., Motegi, H., Inoue, M., Minowa, O., Yoshida, A., Deguchi, K., Sato, H., Ito, S., Shiroishi, T., Takeyasu, K., Noda, T., Fujita, T.
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<strong>Autoimmune disorders associated with gain of function of the intracellular sensor MDA5.</strong>
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Immunity 40: 199-212, 2014.
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[PubMed: 24530055]
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<p class="mim-text-font">
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Gorman, J. A., Hundhausen, C., Errett, J. S., Stone, A. E., Allenspach, E. J., Ge, Y., Arkatkar, T., Clough, C., Dai, X., Khim, S., Pestal, K., Liggitt, D., Cerosaletti, K., Stetson, D. B., James, R. G., Oukka, M., Concannon, P., Gale, M., Buckner, J. H., Rawlings, D. J.
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<strong>The A946T variant of the RNA sensor IFIH1 mediates an interferon program that limits viral infection but increases the risk for autoimmunity.</strong>
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Nature Immun. 18: 744-752, 2017.
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<p class="mim-text-font">
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Kang, D., Gopalkrishnan, R. V., Lin, L., Randolph, A., Valerie, K., Pestka, S., Fisher, P. B.
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<strong>Expression analysis and genomic characterization of human melanoma differentiation associated gene-5, mda-5: a novel type I interferon-responsive apoptosis-inducing gene.</strong>
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<p class="mim-text-font">
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Kang, D., Gopalkrishnan, R. V., Wu, Q., Jankowsky, E., Pyle, A. M., Fisher, P. B.
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<strong>mda-5: an interferon-inducible putative RNA helicase with double-stranded RNA-dependent ATPase activity and melanoma growth-suppressive properties.</strong>
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Proc. Nat. Acad. Sci. 99: 637-642, 2002.
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[PubMed: 11805321]
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<p class="mim-text-font">
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Kato, H., Takeuchi, O., Sato, S., Yoneyama, M., Yamamoto, M., Matsui, K., Uematsu, S., Jung, A., Kawai, T., Ishii, K. J., Yamaguchi, O., Otsu, K., Tsujimura, T., Koh, C.-S., Sousa, C. R., Matsuura, Y., Fujita, T., Akira, S.
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<strong>Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses.</strong>
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Nature 441: 101-105, 2006.
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[PubMed: 16625202]
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<p class="mim-text-font">
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Lamborn, I. T., Jing, H., Zhang, Y., Drutman, S. B., Abbott, J. K., Munir, S., Bade, S., Murdock, H. M., Santos, C. P., Brock, L. G., Masutani, E., Fordjour, E. Y., and 14 others.
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<strong>Recurrent rhinovirus infections in a child with inherited MDA5 deficiency.</strong>
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J. Exp. Med. 214: 1949-1972, 2017.
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[PubMed: 28606988]
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[Full Text: https://doi.org/10.1084/jem.20161759]
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</p>
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<li>
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<p class="mim-text-font">
|
|
Liddicoat, B. J., Piskol, R., Chalk, A. M., Ramaswami, G., Higuchi, M., Hartner, J. C., Li, J. B., Seeburg, P. H., Walkley, C. R.
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|
<strong>RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself.</strong>
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|
Science 349: 1115-1120, 2015.
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[PubMed: 26275108]
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[Full Text: https://doi.org/10.1126/science.aac7049]
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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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Motz, C., Schuhmann, K. M., Kirchhofer, A., Moldt, M., Witte, G., Conzelmann, K.-K., Hopfner, K.-P.
|
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<strong>Paramyxovirus V proteins disrupt the fold of the RNA sensor MDA5 to inhibit antiviral signaling.</strong>
|
|
Science 339: 690-693, 2013.
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[PubMed: 23328395]
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[Full Text: https://doi.org/10.1126/science.1230949]
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Oda, H., Nakagawa, K., Abe, J., Awaya, T., Funabiki, M., Hijikata, A., Nishikomori, R., Funatsuka, M., Ohshima, Y., Sugawara, Y., Yasumi, T., Kato, H., Shirai, T., Ohara, O., Fujita, T., Heike, T.
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Rice, G. I., del Toro Duany, Y., Jenkinson, E. M., Forte, G. M. A., Anderson, B. H., Ariaudo, G., Bader-Meunier, B., Baildam, E. M., Battini, R., Beresford, M. W., Casarano, M., Chouchane, M., and 41 others.
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<strong>Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling.</strong>
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Nature Genet. 46: 503-509, 2014.
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[PubMed: 24686847]
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[Full Text: https://doi.org/10.1038/ng.2933]
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<strong>Oral phenotype of Singleton-Merten syndrome: a systematic review illustrated with a case report.</strong>
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[Full Text: https://doi.org/10.3389/fgene.2022.875490]
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Robinson, T., Kariuki, S. N., Franek, B. S., Kumabe, M., Kumar, A. A., Badaracco, M., Mikolaitis, R. A., Guerrero, G., Utset, T. O., Drevlow, B. E., Zaacks, L. S., Grober, J. S., Cohen, L. M., Kirou, K. A., Crow, M. K., Jolly, M., Niewold, T. B.
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<strong>Autoimmune disease risk variant of IFIH1 is associated with increased sensitivity to IFN-alpha and serologic autoimmunity in lupus patients.</strong>
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J. Immun. 187: 1298-1303, 2011.
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[PubMed: 21705624]
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[Full Text: https://doi.org/10.4049/jimmunol.1100857]
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Rutsch, F., Kehl, H. G., Ruf, N., Vogt, J., Kleinheinz, J., Rauch, F., Hofbauer, L. C., Rehder, H., Arslan-Kirchner, M., Nurnberg, P.
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<strong>Singleton-Merten syndrome: evidence of autosomal dominant inheritance in the first European family. (Abstract)</strong>
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Rutsch, F., MacDougall, M., Lu, C., Buers, I., Mamaeva, O., Nitschke, Y., Rice, G. I., Erlandsen, H., Kehl, H. G., Thiele, H., Nurnberg, P., Hohne, W., Crow, Y. J., Feigenbaum, A., Hennekam, R. C.
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<strong>A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome.</strong>
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Am. J. Hum. Genet. 96: 275-282, 2015.
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Soda, N., Sakai, N., Kato, H., Takami, M., Fujita, T.
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<strong>Singleton-Merten syndrome-like skeletal abnormalities in mice with constitutively activated MDA5.</strong>
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Valverde, I., Rosenthal, E., Tzifa, A., Desai, P., Bell, A., Pushparajah, K., Qureshi, S., Beerbaum, P., Simpson, J.
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<strong>Singleton-Merten syndrome and impaired cardiac function.</strong>
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[PubMed: 21070929]
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Zaki, M., Thoenes, M., Kawalia, A., Nurnberg, P., Kaiser, R., Heller, R., Bolz, H. J.
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<strong>Recurrent and prolonged infections in a child with a homozygous IFIH1 nonsense mutation.</strong>
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